Anti-fibrotic pyridinones

ABSTRACT

Disclosed are pyridinone compounds, method for preparing these compounds, and methods for treating fibrotic disorders.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a divisional of U.S. application Ser. No.14/043,121, filed Oct. 1, 2013, which claims the benefit of priority toU.S. Appl. No. 61/709,075, filed Oct. 2, 2012, U.S. Appl. No.61/777,499, filed Mar. 12, 2013 and U.S. Appl. No. 61/872,157, filedAug. 30, 2013, all of which are hereby incorporated by references intheir entireties.

BACKGROUND

Field

Pyridinone compounds, method of making such compounds, pharmaceuticalcompositions and medicaments comprising such compounds, and methods ofusing such compounds to treat, prevent or diagnose diseases, disorders,or conditions associated with fibrosis are provided.

Description

Fibrosis is the formation of excess fibrous connective tissue in anorgan or tissue in a reparative or reactive process. Examples offibrosis include, but are not limited to pulmonary fibrosis, liverfibrosis, dermal fibrosis, and renal fibrosis. Pulmonary fibrosis, alsocalled idiopathic pulmonary fibrosis (IPF), interstitial diffusepulmonary fibrosis, inflammatory pulmonary fibrosis, or fibrosingalveolitis, is a lung disorder and a heterogeneous group of conditionscharacterized by abnormal formation of fibrous tissue between alveolicaused by alveolitis comprising cellular infiltration into the alveolarseptae with resulting fibrosis. The effects of IPF are chronic,progressive, and often fatal.

There continues to be a need for safe and effective drugs to treatfibrotic conditions such as idiopathic pulmonary fibrosis.

SUMMARY

Some embodiments of the present application provide a compound havingthe structure of formula (I):

or a pharmaceutically acceptable salt thereof, wherein

R¹ is selected from the group consisting of halogen, —CN, —C(O)R⁸,—SO₂R¹⁶, C₁₋₆ alkyl optionally substituted with one or more R⁴, C₂₋₆alkenyl optionally substituted with one or more R⁴, C₂₋₆ alkynyloptionally substituted with one or more R⁴, C₆₋₁₀ aryl optionallysubstituted with one or more R⁴, 5-10 membered heteroaryl optionallysubstituted with one or more R⁴, C₃₋₁₀ carbocyclyl optionallysubstituted with one or more R⁴, and 3-10 membered heterocyclyloptionally substituted with one or more R⁴;

R² is selected from the group consisting of halogen, —CN, —OR⁵, —SR⁵,—NR⁶R⁷, and —C(O)R⁸;

R³ is selected from the group consisting of hydrogen, —(CH₂)_(n)—(C₆₋₁₀aryl), —(CH₂)_(n)-(5-10 membered heteroaryl), —(CH₂)_(n)—(C₃₋₁₀carbocyclyl), and —(CH₂)_(n)-(3-10 membered heterocyclyl), eachoptionally substituted with one or more R⁹;

each R⁴ is independently selected from the group consisting of halogen,—CN, —OH, —C(O)R⁸, —SO₂R¹⁶, optionally substituted C₁₋₆ alkyl,optionally substituted C₂₋₆ alkenyl, optionally substituted C₂₋₆alkynyl, optionally substituted C₁₋₆ alkoxy, optionally substitutedC₆₋₁₀ aryl optionally substituted with one or more R¹¹, C₇₋₁₄ aralkyloptionally substituted with one or more R¹¹, 5-10 membered heteroaryloptionally substituted with one or more R¹¹, or independently twogeminal R⁴ together are oxo;

each R⁵ is independently selected from the group consisting of hydrogen,optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl,optionally substituted C₂₋₆ alkynyl, optionally substituted C₂₋₈alkoxyalkyl, C₆₋₁₀ aryl optionally substituted with one or more R¹¹,C₇₋₁₄ aralkyl optionally substituted with one or more R¹¹, and—(CH₂)_(n)-(3-10 membered heterocyclyl) optionally substituted with oneor more R¹⁰;

R⁶ is selected from the group consisting of hydrogen, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl, optionallysubstituted C₂₋₆ alkynyl, C₆₋₁₀ aryl optionally substituted with one ormore R¹¹, C₇₋₁₄ aralkyl optionally substituted with one or more R¹¹,(5-10 membered heteroaryl)alkyl optionally substituted with one or moreR¹¹, —C(O)R⁸, and —C(O)OR⁵;

R⁷ is selected from the group consisting of hydrogen, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl, optionallysubstituted C₂₋₆ alkynyl, C₆₋₁₀ aryl optionally substituted with one ormore R¹¹, C₇₋₁₄ aralkyl optionally substituted with one or more R¹¹,(5-10 membered heteroaryl)alkyl optionally substituted with one or moreR¹¹, —C(O)R⁸, and —C(O)OR⁵;

or R⁶ and R⁷ together with the nitrogen to which they are attached forma 3-10 membered heterocyclyl optionally substituted with one or moreR¹⁰;

each R⁸ is independently selected from the group consisting of hydrogen,optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl,optionally substituted C₂₋₆ alkynyl, C₆₋₁₀ aryl optionally substitutedwith one or more R¹¹, C₇₋₁₄ aralkyl optionally substituted with one ormore R¹¹, —NR¹²R¹³, and —OR⁵;

each R⁹ is independently selected from the group consisting of hydroxy,halogen, optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆alkenyl, optionally substituted C₂₋₆ alkynyl, optionally substitutedC₁₋₆ alkylthio, optionally substituted C₂₋₈ alkoxyalkyl, optionallysubstituted C₃₋₁₀ carbocyclyl, optionally substituted C₆₋₁₀ aryl, —OR⁵,—NR¹⁴R¹⁵, —C(O)R⁸, —CN, —SO₂R¹⁶, and —NO₂;

each R¹⁰ is independently selected from the group consisting ofoptionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl,and optionally substituted C₂₋₆ alkynyl, or independently two geminalR¹⁰ together are oxo;

each R¹¹ is independently selected from the group consisting of halogen,—CN, optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆alkenyl, optionally substituted C₂₋₆ alkynyl, —O—(CH₂)_(n)—C₁₋₈ alkoxy,—C(O)R⁸, and optionally substituted C₁₋₆ alkoxy;

each R¹² is independently selected from the group consisting ofhydrogen, optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆alkenyl, optionally substituted C₂₋₆ alkynyl, C₆₋₁₀ aryl optionallysubstituted with one or more R¹¹, and C₇₋₁₄ aralkyl optionallysubstituted with one or more R¹¹;

each R¹³ is independently selected from the group consisting ofhydrogen, optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆alkenyl, optionally substituted C₂₋₆ alkynyl, C₆₋₁₀ aryl optionallysubstituted with one or more R¹¹, and C₇₋₁₄ aralkyl optionallysubstituted with one or more R¹¹;

R¹⁴ is selected from the group consisting of hydrogen, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₆₋₁₀ aryl, and —C(O)R⁸;

R¹⁵ is selected from the group consisting of hydrogen, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₆₋₁₀ aryl, and —C(O)R⁸;

each R¹⁶ is independently selected from the group consisting ofoptionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl,optionally substituted C₂₋₆ alkynyl, C₆₋₁₀ aryl optionally substitutedwith one or more R¹¹, C₇₋₁₄ aralkyl optionally substituted with one ormore R¹¹, —NR¹²R¹³, and —OR⁵;

Z is selected from oxygen and sulfur;

each n is independently an integer from 0 to 4; and

the bonds represented by a solid and dashed line are independentlyselected from the group consisting of a single bond and a double bond,provided that

when R³ is H, then R¹ is selected from C₆₋₁₀ aryl optionally substitutedwith one or more R⁴, or 5-10 membered heteroaryl optionally substitutedwith one or more R⁴;

when R² is —NH-(2-fluoro-4-bromo-phenyl) and R¹ is C(O)OH, then R³cannot be —CH₂-phenyl;

when R² is methoxy, R¹ is 4-methoxyphenyl, and Z is O, then R³ is not—(CH₂)-2-fluro-4-chloro-phenyl;

when R³ is a phenyl; R² is OR⁵ or NR⁶R⁷; then R¹ is not triazolyl;

when R³ is 4-methyl phenyl, R² is morpholinyl, and Z is O; then R¹ isnot methyl; and

when R³ is 4-methyl phenyl, R² is —N(CH₃)₂, Z is O; then R¹ is notmethyl.

Some embodiments of the present application provide a compound havingthe structure of formula (II):

or a pharmaceutically acceptable salt thereof, wherein

R² is selected from the group consisting of optionally substituted C₁₋₆alkyl, optionally substituted C₂₋₆ alkenyl, and optionally substitutedC₂₋₆ alkynyl;

R³ is selected from the group consisting of hydrogen, —(CH₂)_(n)—(C₆₋₁₀aryl), —(CH₂)_(n)-(5-10 membered heteroaryl), —(CH₂)_(n)—(C₃₋₁₀carbocyclyl), and —(CH₂)_(n)-(3-10 membered heterocyclyl), eachoptionally substituted with one or more R⁹;

Y is selected from N and CR⁴;

each R⁴ is independently selected from the group consisting of halogen,—CN, —OH, —C(O)R⁸, —SO₂R¹⁶, optionally substituted C₁₋₆ alkyl,optionally substituted C₂₋₆ alkenyl, optionally substituted C₂₋₆alkynyl, optionally substituted C₁₋₆ alkoxy, C₆₋₁₀ aryl optionallysubstituted with one or more R¹¹, C₇₋₁₄ aralkyl optionally substitutedwith one or more R¹¹, 5-10 membered heteroaryl optionally substitutedwith one or more R¹¹,

or independently two adjacent R⁴ together with the carbon atoms to whichthey are attached form a fused ring selected from the group consistingof optionally substituted phenyl, optionally substituted 5-6 memberedheteroaryl, optionally substituted C₃₋₇ carbocyclyl, and optionallysubstituted 3-7 membered heterocyclyl;

each R⁹ is independently selected from the group consisting of hydroxy,halogen, optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆alkenyl, optionally substituted C₂₋₆ alkynyl, optionally substitutedC₁₋₆ alkylthio, optionally substituted C₂₋₈ alkoxyalkyl, optionallysubstituted C₃₋₁₀ carbocyclyl, optionally substituted C₆₋₁₀ aryl, —OR⁵,—NR¹⁴R¹⁵, —C(O)R⁸, —CN, —SO₂R¹⁶, and —NO₂;

R¹⁴ is selected from the group consisting of hydrogen, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₆₋₁₀ aryl, and —C(O)R⁸;

R¹⁵ is selected from the group consisting of hydrogen, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₆₋₁₀ aryl, and —C(O)R⁸;

each R⁸ is independently selected from the group consisting of hydrogen,optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl,optionally substituted C₂₋₆ alkynyl, C₆₋₁₀ aryl optionally substitutedwith one or more R¹¹, C₇₋₁₄ aralkyl optionally substituted with one ormore R¹¹, —NR¹²R¹³, and —OR⁵;

each R¹² is independently selected from the group consisting ofhydrogen, optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆alkenyl, optionally substituted C₂₋₆ alkynyl, C₆₋₁₀ aryl optionallysubstituted with one or more R¹¹, and C₇₋₁₄ aralkyl optionallysubstituted with one or more R¹¹;

each R¹³ is independently selected from the group consisting ofhydrogen, optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆alkenyl, optionally substituted C₂₋₆ alkynyl, C₆₋₁₀ aryl optionallysubstituted with one or more R¹¹, and C₇₋₁₄ aralkyl optionallysubstituted with one or more R¹¹;

each R⁵ is independently selected from the group consisting of hydrogen,optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl,optionally substituted C₂₋₆ alkynyl, optionally substituted C₂₋₈alkoxyalkyl, C₆₋₁₀ aryl optionally substituted with one or more R¹¹,C₇₋₁₄ aralkyl optionally substituted with one or more R¹¹, and—(CH₂)_(n)-(3-10 membered heterocyclyl) optionally substituted with oneor more R¹⁰;

each R¹⁰ is independently selected from the group consisting ofoptionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl,and optionally substituted C₂₋₆ alkynyl, or independently two geminalR¹⁰ together are oxo;

each R¹¹ is independently selected from the group consisting of halogen,—CN, optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆alkenyl, optionally substituted C₂₋₆ alkynyl, and optionally substitutedC₁₋₆ alkoxy;

each R¹⁶ is independently selected from the group consisting ofoptionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl,optionally substituted C₂₋₆ alkynyl, C₆₋₁₀ aryl optionally substitutedwith one or more R¹¹, C₇₋₁₄ aralkyl optionally substituted with one ormore R¹¹, —NR¹²R¹³, and —OR⁵;

Z is selected from oxygen and sulfur;

each n is independently an integer from 0 to 4; and

the bonds represented by a solid and dashed line are independentlyselected from the group consisting of a single bond and a double bond.

In some embodiments, if R is hydrogen, then

is

and the two adjacent R⁴ together with the carbon atoms to which they areattached form a fused ring selected from optionally substituted 5 or 6membered heteroaryl or optionally substituted 5 or 6 memberedheterocyclyl.

Some embodiments of the present application provide a compound havingthe structure of formula (III):

or a pharmaceutically acceptable salt thereof, wherein

R¹ is selected from the group consisting of halogen, —CN, —C(O)R⁸,—SO₂R¹⁶, C₁₋₆ alkyl optionally substituted with one or more R⁴, C₂₋₆alkenyl optionally substituted with one or more R⁴, C₂₋₆ alkynyloptionally substituted with one or more R⁴, C₆₋₁₀ aryl optionallysubstituted with one or more R⁴, 5-10 membered heteroaryl optionallysubstituted with one or more R⁴, C₃₋₁₀ carbocyclyl optionallysubstituted with one or more R⁴, and 3-10 membered heterocyclyloptionally substituted with one or more R⁴;

R³ is selected from the group consisting of hydrogen, —(CH₂)_(n)—(C₆₋₁₀aryl), —(CH₂)_(n)-(5-10 membered heteroaryl), —(CH₂)_(n)—(C₃₋₁₀carbocyclyl), and —(CH₂)_(n)-(3-10 membered heterocyclyl), eachoptionally substituted with one or more R⁹;

ring A is selected from the group consisting of phenyl, 5-6 memberedheteroaryl, C₃₋₇ carbocyclyl, and 3-7 membered heterocyclyl, eachoptionally substituted with one or more R⁴;

each R⁴ is independently selected from the group consisting of halogen,—CN, —OH, —C(O)R⁸, —SO₂R¹⁶, optionally substituted C₁₋₆ alkyl,optionally substituted C₂₋₆ alkenyl, optionally substituted C₂₋₆alkynyl, optionally substituted C₁₋₆ alkoxy, optionally substitutedC₆₋₁₀ aryl optionally substituted with one or more R¹¹, C₇₋₁₄ aralkyloptionally substituted with one or more R¹¹, 5-10 membered heteroaryloptionally substituted with one or more R¹¹, or independently twogeminal R⁴ together are oxo;

each R⁹ is independently selected from the group consisting of hydroxy,halogen, optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆alkenyl, optionally substituted C₂₋₆ alkynyl, optionally substitutedC₁₋₆ alkylthio, optionally substituted C₂₋₈ alkoxyalkyl, optionallysubstituted C₃₋₁₀ carbocyclyl, optionally substituted C₆₋₁₀ aryl, —OR⁵,—NR¹⁴R¹⁵, —C(O)R⁸, —SO₂R¹⁶, —CN and —NO₂;

R¹⁴ is selected from the group consisting of hydrogen, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₆₋₁₀ aryl, and —C(O)R⁸;

R¹⁵ is selected from the group consisting of hydrogen, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₆₋₁₀ aryl, and —C(O)R⁸;

each R⁸ is independently selected from the group consisting of hydrogen,optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl,optionally substituted C₂₋₆ alkynyl, C₆₋₁₀ aryl optionally substitutedwith one or more R¹¹, C₇₋₁₄ aralkyl optionally substituted with one ormore R¹¹, —NR¹²R¹³, and —OR⁵;

each R¹² is independently selected from the group consisting ofhydrogen, optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆alkenyl, optionally substituted C₂₋₆ alkynyl, C₆₋₁₀ aryl optionallysubstituted with one or more R¹¹, and C₇₋₁₄ aralkyl optionallysubstituted with one or more R¹¹;

each R¹³ is independently selected from the group consisting ofhydrogen, optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆alkenyl, optionally substituted C₂₋₆ alkynyl, C₆₋₁₀ aryl optionallysubstituted with one or more R¹¹, and C₇₋₁₄ aralkyl optionallysubstituted with one or more R¹¹;

each R⁵ is independently selected from the group consisting of hydrogen,optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl,optionally substituted C₂₋₆ alkynyl, optionally substituted C₂₋₈alkoxyalkyl, C₆₋₁₀ aryl optionally substituted with one or more R¹¹,C₇₋₁₄ aralkyl optionally substituted with one or more R¹¹, and—(CH₂)_(n)-(3-10 membered heterocyclyl) optionally substituted with oneor more R¹⁰;

each R¹⁰ is independently selected from the group consisting ofoptionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl,and optionally substituted C₂₋₆ alkynyl, or independently two geminalR¹⁰ together are oxo;

each R¹¹ is independently selected from the group consisting of halogen,—CN, optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆alkenyl, optionally substituted C₂₋₆ alkynyl, and optionally substitutedC₁₋₆ alkoxy;

each R¹⁶ is independently selected from the group consisting ofoptionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl,optionally substituted C₂₋₆ alkynyl, C₆₋₁₀ aryl optionally substitutedwith one or more R¹¹, C₇₋₁₄ aralkyl optionally substituted with one ormore R¹¹, —NR¹²R¹³, and —OR⁵;

Z is selected from oxygen and sulfur;

each n is independently an integer from 0 to 4; and

the bonds represented by a solid and dashed line are independentlyselected from the group consisting of a single bond and a double bond,provided that

when R³ is H, then R¹ is selected from C₆₋₁₀ aryl optionally substitutedwith one or more R⁴, or 5-10 membered heteroaryl optionally substitutedwith one or more R⁴;

when R³ is phenyl optionally substituted with one or more R⁹, and Z isO; then ring A cannot be optionally substituted phenyl;

when ring A is selected from cyclopentenyl, optionally substitutedpyrrolyl or optionally substituted dihydropyrrolidinyl, R³ is phenyloptionally substituted with one or more R⁹, and Z is O; then R¹ is nothalogen, 3-methoxy phenyl or 3,5-dimethoxy phenyl;

when ring A is pyridyl, R¹ is optionally substituted phenyl, and Z is O;then n in R³ is zero and R³ is not halogen substituted phenyl;

when ring A is optionally substituted pyrimidyl, R³ is phenyl or benzyl,and Z is O; then R¹ is not methyl or benzyl;

when ring A is optionally substituted furanyl, R³ is phenyl optionallysubstituted with one or more R⁹, and Z is O; then R¹ is not fluoro;

when ring A is optionally substituted pyrrolyl, R³ is phenyl optionallysubstituted with one or more R⁹, and Z is O; then R¹ is not methyl;

when ring A is tetrahydrofuranyl, R³ is phenyl, and Z is O; then R¹ isnot methyl or phenyl; and

when ring A is pyradizinyl, R³ is 4-NO₂-phenyl, and Z is O; then R¹ isnot methyl.

Some embodiments of the present application provide a compound, havingthe structure of formula (IV):

or a pharmaceutically acceptable salt thereof, wherein

R¹ is selected from the group consisting of hydrogen, C₁₋₆ alkyloptionally substituted with one or more R⁴, C₂₋₆ alkenyl optionallysubstituted with one or more R⁴, C₂₋₆ alkynyl optionally substitutedwith one or more R⁴, C₆₋₁₀ aryl optionally substituted with one or moreR⁴, 5-10 membered heteroaryl optionally substituted with one or more R⁴,C₃₋₁₀ carbocyclyl optionally substituted with one or more R⁴, and 3-10membered heterocyclyl optionally substituted with one or more R⁴;

each R² is independently selected from the group consisting of hydrogen,halogen, optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆alkenyl, optionally substituted C₂₋₆ alkynyl, —CN, —OR⁵, —NR⁶R⁷, and—C(O)R⁸,

or both R² together with the carbon atoms to which they are attachedform a fused ring selected from the group consisting of phenyl, 5-6membered heteroaryl, C₃₋₇ carbocyclyl, and 3-7 membered heterocyclyl,each optionally substituted with one or more R⁴;

each R⁴ is independently selected from the group consisting of halogen,—CN, optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆alkenyl, optionally substituted C₂₋₆ alkynyl, and optionally substitutedC₁₋₆ alkoxy;

each R⁵ is independently selected from the group consisting of hydrogen,optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl,optionally substituted C₂₋₆ alkynyl, optionally substituted C₂₋₈alkoxyalkyl, C₆₋₁₀ aryl optionally substituted with one or more R¹¹,C₇₋₁₄ aralkyl optionally substituted with one or more R¹¹,—(CH₂)_(n)-(3-10 membered heterocyclyl) optionally substituted with oneor more R¹⁰, and —(CH₂)_(n)—(C₆₋₁₀ aryl) optionally substituted with oneor more R¹¹;

R⁶ is selected from the group consisting of hydrogen, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl, optionallysubstituted C₂₋₆ alkynyl, C₆₋₁₀ aryl optionally substituted with one ormore R¹¹, C₇₋₁₄ aralkyl optionally substituted with one or more R¹¹,(5-10 membered heteroaryl)alkyl optionally substituted with one or moreR¹¹, —C(O)R⁸, and —C(O)OR⁵;

R⁷ is selected from the group consisting of hydrogen, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl, optionallysubstituted C₂₋₆ alkynyl, C₆₋₁₀ aryl optionally substituted with one ormore R¹¹, C₇₋₁₄ aralkyl optionally substituted with one or more R¹¹,(5-10 membered heteroaryl)alkyl optionally substituted with one or moreR¹¹, —C(O)R⁸, and —C(O)OR⁵;

or R⁶ and R⁷ together with the nitrogen to which they are attached forman 3-10 membered heterocyclyl optionally substituted with one or moreR¹⁰;

each R⁸ is independently selected from the group consisting ofoptionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl,optionally substituted C₂₋₆ alkynyl, —NR¹²R¹³, and —OR⁵;

each Y is independently N or CR⁹;

each R⁹ is independently selected from the group consisting of halogen,optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl,optionally substituted C₂₋₆ alkynyl, optionally substituted C₁₋₆ alkoxy,and —NR¹⁴R¹⁵,

or independently two adjacent R⁹ together with the ring atoms to whichthey are attached form a fused optionally substituted 3-10 memberedheterocyclyl or a fused optionally substituted 5-10 membered heteroaryl;

each R¹⁰ is independently selected from the group consisting of oxo,optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl,and optionally substituted C₂₋₆ alkynyl;

each R¹¹ is independently selected from the group consisting of halogen,—CN, optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆alkenyl, optionally substituted C₂₋₆ alkynyl, and optionally substitutedC₁₋₆ alkoxy;

each R¹² is independently selected from the group consisting ofhydrogen, optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆alkenyl, optionally substituted C₂₋₆ alkynyl, C₆₋₁₀ aryl optionallysubstituted with one or more R¹¹, and C₇₋₁₄ aralkyl optionallysubstituted with one or more R¹¹;

each R¹³ is independently selected from the group consisting ofhydrogen, optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆alkenyl, optionally substituted C₂₋₆ alkynyl, C₆₋₁₀ aryl optionallysubstituted with one or more R¹¹, and C₇₋₁₄ aralkyl optionallysubstituted with one or more R¹¹;

R¹⁴ is selected from the group consisting of hydrogen, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₆₋₁₀ aryl, and —C(O)R⁸;

R¹⁵ is selected from the group consisting of hydrogen, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₆₋₁₀ aryl, and —C(O)R⁸;

Z is selected from oxygen and sulfur;

n is an integer from 0 to 4;

m is an integer from 1 to 4; and

the bonds represented by a solid and dashed line are independentlyselected from the group consisting of a single bond and a double bond.

Some embodiments of the present application provide a compound havingthe structure of formula (V):

or a pharmaceutically acceptable salt thereof, wherein

A is a C₅₋₇ carbocyclyl optionally substituted with one or more R⁴;

each R² is independently selected from the group consisting of hydrogen,halogen, optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆alkenyl, optionally substituted C₂₋₆ alkynyl, —CN, —OR⁵, —NR⁶R⁷, and—C(O)R⁸,

or both R² together with the carbon atoms to which they are attachedform a fused ring selected from the group consisting of phenyl, 5-6membered heteroaryl, C₃₋₇ carbocyclyl, and 3-7 membered heterocyclyl,each optionally substituted with one or more R⁴;

R³ is selected from the group consisting of —(CH₂)_(n)—(C₆₋₁₀ aryl),—(CH₂)_(n)-(5-10 membered hetero aryl), —(CH₂)_(n)—(C₃₋₁₀ carbocyclyl),and —(CH₂)_(n)-(3-10 membered heterocyclyl), each optionally substitutedwith one or more R⁹;

each R⁴ is independently selected from the group consisting of halogen,—CN, —OH, —C(O)R⁸, —SO₂R¹⁶, optionally substituted C₁₋₆ alkyl,optionally substituted C₂₋₆ alkenyl, optionally substituted C₂₋₆alkynyl, optionally substituted C₁₋₆ alkoxy, optionally substitutedC₆₋₁₀ aryl optionally substituted with one or more R¹¹, C₇₋₁₄ aralkyloptionally substituted with one or more R¹¹, 5-10 membered heteroaryloptionally substituted with one or more R¹¹, or independently twogeminal R⁴ together are oxo;

each R⁵ is independently selected from the group consisting of hydrogen,optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl,optionally substituted C₂₋₆ alkynyl, optionally substituted C₂₋₈alkoxyalkyl, C₆₋₁₀ aryl optionally substituted with one or more R¹¹,C₇₋₁₄ aralkyl optionally substituted with one or more R¹¹, and—(CH₂)_(n)-(3-10 membered heterocyclyl) optionally substituted with oneor more R¹⁰;

R⁶ is selected from the group consisting of hydrogen, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl, optionallysubstituted C₂₋₆ alkynyl, C₆₋₁₀ aryl optionally substituted with one ormore R¹¹, C₇₋₁₄ aralkyl optionally substituted with one or more R¹¹,(5-10 membered heteroaryl)alkyl optionally substituted with one or moreR¹¹, —C(O)R⁸, and —C(O)OR⁵;

R⁷ is selected from the group consisting of hydrogen, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl, optionallysubstituted C₂₋₆ alkynyl, C₆₋₁₀ aryl optionally substituted with one ormore R¹¹, C₇₋₁₄ aralkyl optionally substituted with one or more R¹¹,(5-10 membered heteroaryl)alkyl optionally substituted with one or moreR¹¹, —C(O)R⁸, and —C(O)OR⁵;

or R⁶ and R⁷ together with the nitrogen to which they are attached forman 3-10 membered heterocyclyl optionally substituted with one or moreR¹⁰;

each R⁸ is independently selected from the group consisting of hydrogen,optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl,optionally substituted C₂₋₆ alkynyl, C₆₋₁₀ aryl optionally substitutedwith one or more R¹¹, C₇₋₁₄ aralkyl optionally substituted with one ormore R¹¹, —NR¹²R¹³, and —OR⁵;

each R⁹ is independently selected from the group consisting of halogen,optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl,optionally substituted C₂₋₆ alkynyl, optionally substituted C₁₋₆alkylthio, optionally substituted C₂₋₈ alkoxyalkyl, optionallysubstituted C₃₋₁₀ carbocyclyl, optionally substituted C₆₋₁₀ aryl, —OR⁵,—NR¹⁴R¹⁵, —C(O)R⁸, —SO₂R¹⁶, and —NO₂;

each R¹⁰ is independently selected from the group consisting ofoptionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl,and optionally substituted C₂₋₆ alkynyl, or independently two geminalR¹⁰ together are oxo;

each R¹¹ is independently selected from the group consisting of halogen,—CN, optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆alkenyl, optionally substituted C₂₋₆ alkynyl, and optionally substitutedC₁₋₆ alkoxy;

each R¹² is independently selected from the group consisting ofhydrogen, optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆alkenyl, optionally substituted C₂₋₆ alkynyl, C₆₋₁₀ aryl optionallysubstituted with one or more R¹¹, and C₇₋₁₄ aralkyl optionallysubstituted with one or more R¹¹;

each R¹³ is independently selected from the group consisting ofhydrogen, optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆alkenyl, optionally substituted C₂₋₆ alkynyl, C₆₋₁₀ aryl optionallysubstituted with one or more R¹¹, and C₇₋₁₄ aralkyl optionallysubstituted with one or more R¹¹;

R¹⁴ is selected from the group consisting of hydrogen, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₆₋₁₀ aryl, and —C(O)R⁸;

R¹⁵ is selected from the group consisting of hydrogen, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₆₋₁₀ aryl, and —C(O)R⁸;

each R¹⁶ is independently selected from the group consisting ofoptionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl,optionally substituted C₂₋₆ alkynyl, C₆₋₁₀ aryl optionally substitutedwith one or more R¹¹, C₇₋₁₄ aralkyl optionally substituted with one ormore R¹¹, —NR¹²R¹³, and —OR⁵;

Z is selected from oxygen and sulfur;

each n is independently an integer from 0 to 4; and

the bonds represented by a solid and dashed line are independentlyselected from the group consisting of a single bond and a double bond.

Some embodiments of the present application provide a compound havingthe structure of formula (VIa):

or a pharmaceutically acceptable salt thereof, wherein

R¹ is a C₄₋₇ carbocyclyl optionally substituted with one or more R⁴;

each R² is independently selected from the group consisting of hydrogen,halogen, optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆alkenyl, optionally substituted C₂₋₆ alkynyl, —CN, —OR⁵, —NR⁶R⁷, and—C(O)R⁸,

or both R² together with the carbon atoms to which they are attachedform a fused ring selected from the group consisting of phenyl, 5-6membered heteroaryl, C₃₋₇ carbocyclyl, and 3-7 membered heterocyclyl,each optionally substituted with one or more R⁴;

R³ is selected from the group consisting of —(CH₂)_(n)—(C₆₋₁₀ aryl),—(CH₂)_(n)-(5-10 membered heteroaryl), —(CH₂)_(n)—(C₃₋₁₀ carbocyclyl),and —(CH₂)_(n)-(3-10 membered heterocyclyl), each optionally substitutedwith one or more R⁹;

each R⁴ is independently selected from the group consisting of halogen,—CN, —OH, —C(O)R⁸, —SO₂R¹⁶, optionally substituted C₁₋₆ alkyl,optionally substituted C₂₋₆ alkenyl, optionally substituted C₂₋₆alkynyl, optionally substituted C₁₋₆ alkoxy, optionally substitutedC₆₋₁₀ aryl optionally substituted with one or more R¹¹, C₇₋₁₄ aralkyloptionally substituted with one or more R¹¹, 5-10 membered heteroaryloptionally substituted with one or more R¹¹, or independently twogeminal R⁴ together are oxo;

each R⁵ is independently selected from the group consisting of hydrogen,optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl,optionally substituted C₂₋₆ alkynyl, optionally substituted C₂₋₈alkoxyalkyl, C₆₋₁₀ aryl optionally substituted with one or more R¹¹,C₇₋₁₄ aralkyl optionally substituted with one or more R¹¹, and—(CH₂)_(n)-(3-10 membered heterocyclyl) optionally substituted with oneor more R¹⁰;

R⁶ is selected from the group consisting of hydrogen, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl, optionallysubstituted C₂₋₆ alkynyl, C₆₋₁₀ aryl optionally substituted with one ormore R¹¹, C₇₋₁₄ aralkyl optionally substituted with one or more R¹¹,(5-10 membered heteroaryl)alkyl optionally substituted with one or moreR¹¹, —C(O)R⁸, and —C(O)OR⁵;

R⁷ is selected from the group consisting of hydrogen, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl, optionallysubstituted C₂₋₆ alkynyl, C₆₋₁₀ aryl optionally substituted with one ormore R¹¹, C₇₋₁₄ aralkyl optionally substituted with one or more R¹¹,(5-10 membered heteroaryl)alkyl optionally substituted with one or moreR¹¹, —C(O)R⁸, and —C(O)OR⁵;

or R⁶ and R⁷ together with the nitrogen to which they are attached forman 3-10 membered heterocyclyl optionally substituted with one or moreR¹⁰;

each R⁸ is independently selected from the group consisting of hydrogen,optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl,optionally substituted C₂₋₆ alkynyl, C₆₋₁₀ aryl optionally substitutedwith one or more R¹¹, C₇₋₁₄ aralkyl optionally substituted with one ormore R¹¹, —NR¹²R¹³, and —OR⁵;

each R⁹ is independently selected from the group consisting of halogen,optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl,optionally substituted C₂₋₆ alkynyl, optionally substituted C₁₋₆alkylthio, optionally substituted C₂₋₈ alkoxyalkyl, optionallysubstituted C₃₋₁₀ carbocyclyl, optionally substituted C₆₋₁₀ aryl, —OR⁵,—NR¹⁴R¹⁵, —C(O)R⁸, —SO₂R¹⁶, and —NO₂;

each R¹⁰ is independently selected from the group consisting ofoptionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl,and optionally substituted C₂₋₆ alkynyl, or independently two geminalR¹⁰ together are oxo;

each R¹¹ is independently selected from the group consisting of halogen,—CN, optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆alkenyl, optionally substituted C₂₋₆ alkynyl, and optionally substitutedC₁₋₆ alkoxy;

each R¹² is independently selected from the group consisting ofhydrogen, optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆alkenyl, optionally substituted C₂₋₆ alkynyl, C₆₋₁₀ aryl optionallysubstituted with one or more R¹¹, and C₇₋₁₄ aralkyl optionallysubstituted with one or more R¹¹;

each R¹³ is independently selected from the group consisting ofhydrogen, optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆alkenyl, optionally substituted C₂₋₆ alkynyl, C₆₋₁₀ aryl optionallysubstituted with one or more R¹¹, and C₇₋₁₄ aralkyl optionallysubstituted with one or more R¹¹;

R¹⁴ is selected from the group consisting of hydrogen, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₆₋₁₀ aryl, and —C(O)R⁸;

R¹⁵ is selected from the group consisting of hydrogen, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₆₋₁₀ aryl, and —C(O)R⁸;

each R¹⁶ is independently selected from the group consisting ofoptionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl,optionally substituted C₂₋₆ alkynyl, C₆₋₁₀ aryl optionally substitutedwith one or more R¹¹, C₇₋₁₄ aralkyl optionally substituted with one ormore R¹¹, —NR¹²R¹³, and —OR⁵;

Z is selected from oxygen and sulfur;

each n is independently an integer from 0 to 4; and

the bonds represented by a solid and dashed line are independentlyselected from the group consisting of a single bond and a double bond.

Some embodiments of the present application provide a compound havingthe structure of formula (VII):

or a pharmaceutically acceptable salt thereof, wherein

each R² is independently selected from the group consisting of hydrogen,halogen, optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆alkenyl, optionally substituted C₂₋₆ alkynyl, —CN, —OR⁵, —NR⁶R⁷, and—C(O)R⁸,

or both R² together with the carbon atoms to which they are attachedform a fused ring selected from the group consisting of phenyl, 5-6membered heteroaryl, C₃₋₇ carbocyclyl, and 3-7 membered heterocyclyl,each optionally substituted with one or more R⁴;

R³ is selected from the group consisting of —(CH₂)_(n)—(C₆₋₁₀ aryl),—(CH₂)_(n)-(5-10 membered heteroaryl), —(CH₂)_(n)—(C₃₋₁₀ carbocyclyl),and —(CH₂)_(n)-(3-10 membered heterocyclyl), each optionally substitutedwith one or more R⁹;

each R⁴ is independently selected from the group consisting of halogen,—CN, —OH, —C(O)R⁸, —SO₂R¹⁶, optionally substituted C₁₋₆ alkyl,optionally substituted C₂₋₆ alkenyl, optionally substituted C₂₋₆alkynyl, optionally substituted C₁₋₆ alkoxy, optionally substitutedC₆₋₁₀ aryl optionally substituted with one or more R¹¹, C₇₋₁₄ aralkyloptionally substituted with one or more R¹¹, 5-10 membered heteroaryloptionally substituted with one or more R¹¹, or independently twogeminal R⁴ together are oxo;

each R⁵ is independently selected from the group consisting of hydrogen,optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl,optionally substituted C₂₋₆ alkynyl, optionally substituted C₂₋₈alkoxyalkyl, C₆₋₁₀ aryl optionally substituted with one or more R¹¹,C₇₋₁₄ aralkyl optionally substituted with one or more R¹¹, and—(CH₂)_(n)-(3-10 membered heterocyclyl) optionally substituted with oneor more R¹⁰;

R⁶ is selected from the group consisting of hydrogen, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl, optionallysubstituted C₂₋₆ alkynyl, C₆₋₁₀ aryl optionally substituted with one ormore R¹¹, C₇₋₁₄ aralkyl optionally substituted with one or more R¹¹,(5-10 membered heteroaryl)alkyl optionally substituted with one or moreR¹¹, —C(O)R⁸, and —C(O)OR⁵;

R⁷ is selected from the group consisting of hydrogen, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl, optionallysubstituted C₂₋₆ alkynyl, C₆₋₁₀ aryl optionally substituted with one ormore R¹¹, C₇₋₁₄ aralkyl optionally substituted with one or more R¹¹,(5-10 membered heteroaryl)alkyl optionally substituted with one or moreR¹¹, —C(O)R⁸, and —C(O)OR⁵;

or R⁶ and R⁷ together with the nitrogen to which they are attached forman 3-10 membered heterocyclyl optionally substituted with one or moreR¹⁰;

each R⁸ is independently selected from the group consisting of hydrogen,optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl,optionally substituted C₂₋₆ alkynyl, C₆₋₁₀ aryl optionally substitutedwith one or more R¹¹, C₇₋₁₄ aralkyl optionally substituted with one ormore R¹¹, —NR¹²R¹³, and —OR⁵;

each R⁹ is independently selected from the group consisting of halogen,optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl,optionally substituted C₂₋₆ alkynyl, optionally substituted C₁₋₆alkylthio, optionally substituted C₂₋₈ alkoxyalkyl, optionallysubstituted C₃₋₁₀ carbocyclyl, optionally substituted C₆₋₁₀ aryl, —OR⁵,—NR¹⁴R¹⁵, —C(O)R⁸, —SO₂R¹⁶, and —NO₂;

each R¹⁰ is independently selected from the group consisting ofoptionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl,and optionally substituted C₂₋₆ alkynyl, or independently two geminalR¹⁰ together are oxo;

each R¹¹ is independently selected from the group consisting of halogen,—CN, optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆alkenyl, optionally substituted C₂₋₆ alkynyl, and optionally substitutedC₁₋₆ alkoxy;

each R¹² is independently selected from the group consisting ofhydrogen, optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆alkenyl, optionally substituted C₂₋₆ alkynyl, C₆₋₁₀ aryl optionallysubstituted with one or more R¹¹, and C₇₋₁₄ aralkyl optionallysubstituted with one or more R¹¹;

each R¹³ is independently selected from the group consisting ofhydrogen, optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆alkenyl, optionally substituted C₂₋₆ alkynyl, C₆₋₁₀ aryl optionallysubstituted with one or more R¹¹, and C₇₋₁₄ aralkyl optionallysubstituted with one or more R¹¹;

R¹⁴ is selected from the group consisting of hydrogen, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₆₋₁₀ aryl, and —C(O)R⁸;

R¹⁵ is selected from the group consisting of hydrogen, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₆₋₁₀ aryl, and —C(O)R⁸;

Q is selected from C(O) and S(O)_(t);

each R¹⁶ is independently selected from the group consisting ofoptionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl,optionally substituted C₂₋₆ alkynyl, C₆₋₁₀ aryl optionally substitutedwith one or more R¹¹, C₇₋₁₄ aralkyl optionally substituted with one ormore R¹¹, —NR¹²R¹³, and —OR⁵;

Z is selected from oxygen and sulfur;

each n is independently an integer from 0 to 4;

t is 1 or 2; and

the bonds represented by a solid and dashed line are independentlyselected from the group consisting of a single bond and a double bond.

Some embodiments of the present application provide a compound havingthe structure of formula (VIb):

R¹ is selected from the group consisting of halogen, —CN, —C(O)R⁸,—SO₂R¹⁶, C₁₋₆ alkyl optionally substituted with one or more R⁴, C₂₋₆alkenyl optionally substituted with one or more R⁴, C₂₋₆ alkynyloptionally substituted with one or more R⁴, C₆₋₁₀ aryl optionallysubstituted with one or more R⁴, 5-10 membered heteroaryl optionallysubstituted with one or more R⁴, C₃₋₁₀ carbocyclyl optionallysubstituted with one or more R⁴, and 3-10 membered heterocyclyloptionally substituted with one or more R⁴;

each R² is independently selected from the group consisting of hydrogen,halogen, optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆alkenyl, optionally substituted C₂₋₆ alkynyl, —CN, —OR⁵, —NR⁶R⁷, and—C(O)R⁸,

or both R² together with the carbon atoms to which they are attachedform a fused ring selected from the group consisting of phenyl, 5-6membered heteroaryl, C₃₋₇ carbocyclyl, and 3-7 membered heterocyclyl,each optionally substituted with one or more R⁴;

R³ is selected from the group consisting of —(CH₂)₁₋₄—(C₆₋₁₀ aryl),—(CH₂)₁₋₄-(5-10 membered heteroaryl), —(CH₂)₁₋₄—(C₃₋₁₀ carbocyclyl), and—(CH₂)₁₋₄-(3-10 membered heterocyclyl), each optionally substituted withone or more R⁹;

each R⁴ is independently selected from the group consisting of halogen,—CN, —OH, —C(O)R⁸, —SO₂R¹⁶, optionally substituted C₁₋₆ alkyl,optionally substituted C₂₋₆ alkenyl, optionally substituted C₂₋₆alkynyl, optionally substituted C₁₋₆ alkoxy, optionally substitutedC₆₋₁₀ aryl optionally substituted with one or more R¹¹, C₇₋₁₄ aralkyloptionally substituted with one or more R¹¹, 5-10 membered heteroaryloptionally substituted with one or more R¹¹, or independently twogeminal R⁴ together are oxo;

each R⁵ is independently selected from the group consisting of hydrogen,optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl,optionally substituted C₂₋₆ alkynyl, optionally substituted C₂₋₈alkoxyalkyl, C₆₋₁₀ aryl optionally substituted with one or more R¹¹,C₇₋₁₄ aralkyl optionally substituted with one or more R¹¹, and—(CH₂)_(n)-(3-10 membered heterocyclyl) optionally substituted with oneor more R¹⁰;

R⁶ is selected from the group consisting of hydrogen, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl, optionallysubstituted C₂₋₆ alkynyl, C₆₋₁₀ aryl optionally substituted with one ormore R¹¹, C₇₋₁₄ aralkyl optionally substituted with one or more R¹¹,(5-10 membered heteroaryl)alkyl optionally substituted with one or moreR¹¹, —C(O)R⁸, and —C(O)OR⁵;

R⁷ is selected from the group consisting of hydrogen, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl, optionallysubstituted C₂₋₆ alkynyl, C₆₋₁₀ aryl optionally substituted with one ormore R¹¹, C₇₋₁₄ aralkyl optionally substituted with one or more R¹¹,(5-10 membered heteroaryl)alkyl optionally substituted with one or moreR¹¹, —C(O)R⁸, and —C(O)OR⁵;

or R⁶ and R⁷ together with the nitrogen to which they are attached forman 3-10 membered heterocyclyl optionally substituted with one or moreR¹⁰;

each R⁸ is independently selected from the group consisting of hydrogen,optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl,optionally substituted C₂₋₆ alkynyl, C₆₋₁₀ aryl optionally substitutedwith one or more R¹¹, C₇₋₁₄ aralkyl optionally substituted with one ormore R¹¹, —NR¹²R¹³, and —OR⁵;

each R⁹ is independently selected from the group consisting of halogen,optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl,optionally substituted C₂₋₆ alkynyl, optionally substituted C₁₋₆alkylthio, optionally substituted C₂₋₈ alkoxyalkyl, optionallysubstituted C₃₋₁₀ carbocyclyl, optionally substituted C₆₋₁₀ aryl, —OR⁵,—NR¹⁴R¹⁵, —C(O)R⁸, —SO₂R¹⁶, and —NO₂;

each R¹⁰ is independently selected from the group consisting ofoptionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl,and optionally substituted C₂₋₆ alkynyl, or independently two geminalR¹⁰ together are oxo;

each R¹¹ is independently selected from the group consisting of halogen,—CN, optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆alkenyl, optionally substituted C₂₋₆ alkynyl, and optionally substitutedC₁₋₆ alkoxy;

each R¹² is independently selected from the group consisting ofhydrogen, optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆alkenyl, optionally substituted C₂₋₆ alkynyl, C₆₋₁₀ aryl optionallysubstituted with one or more R¹¹, and C₇₋₁₄ aralkyl optionallysubstituted with one or more R¹¹;

each R¹³ is independently selected from the group consisting ofhydrogen, optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆alkenyl, optionally substituted C₂₋₆ alkynyl, C₆₋₁₀ aryl optionallysubstituted with one or more R¹¹, and C₇₋₁₄ aralkyl optionallysubstituted with one or more R¹¹;

R¹⁴ is selected from the group consisting of hydrogen, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₆₋₁₀ aryl, and —C(O)R⁸;

R¹⁵ is selected from the group consisting of hydrogen, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₆₋₁₀ aryl, and —C(O)R⁸;

each R¹⁶ is independently selected from the group consisting ofoptionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl,optionally substituted C₂₋₆ alkynyl, C₆₋₁₀ aryl optionally substitutedwith one or more R¹¹, C₇₋₁₄ aralkyl optionally substituted with one ormore R¹¹, —NR¹²R¹³, and —OR⁵;

Z is selected from oxygen and sulfur;

each n is independently an integer from 0 to 4; and

the bonds represented by a solid and dashed line are independentlyselected from the group consisting of a single bond and a double bond;provided that

when R¹ is selected from the group consisting of optionally substitutedC₆₋₁₀ aryl, optionally substituted 5 to 10 membered heteroaryl,optionally substituted 6 to 10 membered heterocyclyl, optionallysubstituted hexyl, optionally substituted alkyl, optionally substitutedalkenyl; each of R² is hydrogen or one of R² is hydrogen and the otherR² is methyl; and Z is O; then R³ is not —CH₂-phenyl substituted withone or more halogen atoms; and provided that

R¹ is not 4-methoxy phenyl.

Some embodiments of the present application provide a compound havingthe structure of formula (VIII):

R³ is selected from the group consisting of optionally substituted C₁₋₆alkyl, optionally substituted C₂₋₆ alkenyl, optionally substituted C₂₋₆alkynyl, —(CH₂)_(n)—(C₆₋₁₀ aryl) optionally substituted with one or moreR⁹, —(CH₂)_(n)-(5-10 membered heteroaryl) optionally substituted withone or more R⁹, —(CH₂)_(n)—(C₃₋₁₀ carbocyclyl) optionally substitutedwith one or more R⁹, and —(CH₂)_(n)-(3-10 membered heterocyclyl)optionally substituted with one or more R⁹;

each R⁹ is independently selected from the group consisting of halogen,optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl,optionally substituted C₂₋₆ alkynyl, optionally substituted C₁₋₆alkylthio, optionally substituted C₂₋₈ alkoxyalkyl, optionallysubstituted C₃₋₁₀ carbocyclyl, optionally substituted C₆₋₁₀ aryl, —OR⁵,—NR¹⁴R¹⁵, —C(O)R⁸, —SO₂R¹⁶, and —NO₂;

R¹⁴ is selected from the group consisting of hydrogen, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₆₋₁₀ aryl, and —C(O)R⁸;

R¹⁵ is selected from the group consisting of hydrogen, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₆₋₁₀ aryl, and —C(O)R⁸;

each R⁸ is independently selected from the group consisting of hydrogen,optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl,optionally substituted C₂₋₆ alkynyl, C₆₋₁₀ aryl optionally substitutedwith one or more R¹¹, C₇₋₁₄ aralkyl optionally substituted with one ormore R¹¹, —NR¹²R¹³, and —OR⁵;

each R¹² is independently selected from the group consisting ofhydrogen, optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆alkenyl, optionally substituted C₂₋₆ alkynyl, C₆₋₁₀ aryl optionallysubstituted with one or more R¹¹, and C₇₋₁₄ aralkyl optionallysubstituted with one or more R¹¹;

each R¹³ is independently selected from the group consisting ofhydrogen, optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆alkenyl, optionally substituted C₂₋₆ alkynyl, C₆₋₁₀ aryl optionallysubstituted with one or more R¹¹, and C₇₋₁₄ aralkyl optionallysubstituted with one or more R¹¹;

each R⁵ is independently selected from the group consisting of hydrogen,optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl,optionally substituted C₂₋₆ alkynyl, optionally substituted C₂₋₈alkoxyalkyl, C₆₋₁₀ aryl optionally substituted with one or more R¹¹,C₇₋₁₄ aralkyl optionally substituted with one or more R¹¹, and—(CH₂)_(n)-(3-10 membered heterocyclyl) optionally substituted with oneor more R¹⁰;

each R¹⁰ is independently selected from the group consisting ofoptionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl,and optionally substituted C₂₋₆ alkynyl, or independently two geminalR¹⁰ together are oxo;

each R¹¹ is independently selected from the group consisting of halogen,—CN, optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆alkenyl, optionally substituted C₂₋₆ alkynyl, and optionally substitutedC₁₋₆ alkoxy;

each R¹⁷ is independently selected from the group consisting ofhydrogen, oxo, halogen, —CN, —C(O)R⁸, —SO₂R¹⁶, C₁₋₆ alkyl optionallysubstituted with one or more R⁴, C₂₋₆ alkenyl optionally substitutedwith one or more R⁴, C₂₋₆ alkynyl optionally substituted with one ormore R⁴, C₆₋₁₀ aryl optionally substituted with one or more R⁴, 5-10membered heteroaryl optionally substituted with one or more R⁴, C₃₋₁₀carbocyclyl optionally substituted with one or more R⁴, and 3-10membered heterocyclyl optionally substituted with one or more R⁴,

or independently two adjacent R¹⁷ together with the carbon atoms towhich they are attached form a fused phenyl or 5-6 membered heteroaryl,each optionally substituted with one or more R⁴;

each R⁴ is independently selected from the group consisting of halogen,—CN, —OH, —C(O)R⁸, —SO₂R¹⁶, optionally substituted C₁₋₆ alkyl,optionally substituted C₂₋₆ alkenyl, optionally substituted C₂₋₆alkynyl, optionally substituted C₁₋₆ alkoxy, optionally substitutedC₆₋₁₀ aryl optionally substituted with one or more R¹¹, C₇₋₁₄ aralkyloptionally substituted with one or more R¹¹, 5-10 membered heteroaryloptionally substituted with one or more R¹¹, or independently twogeminal R⁴ together are oxo;

each R¹⁶ is independently selected from the group consisting ofoptionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl,optionally substituted C₂₋₆ alkynyl, C₆₋₁₀ aryl optionally substitutedwith one or more R¹¹, C₇₋₁₄ aralkyl optionally substituted with one ormore R¹¹, —NR¹²R¹³, and —OR⁵;

Z is selected from oxygen and sulfur;

each n is independently an integer from 0 to 4;

s is 0, 1, or 3; and

the bonds represented by a solid and dashed line are independentlyselected from the group consisting of a single bond and a double bond.

Some embodiments of the present application provide a compound havingthe structure of formula (IX):

R¹ is selected from the group consisting of hydrogen, halogen, —CN,—C(O)R⁸, —SO₂R¹⁶, C₁₋₆ alkyl optionally substituted with one or more R⁴,C₂₋₆ alkenyl optionally substituted with one or more R⁴, C₂₋₆ alkynyloptionally substituted with one or more R⁴, C₆₋₁₀ aryl optionallysubstituted with one or more R⁴, 5-10 membered heteroaryl optionallysubstituted with one or more R⁴, C₃₋₁₀ carbocyclyl optionallysubstituted with one or more R⁴, and 3-10 membered heterocyclyloptionally substituted with one or more R⁴;

each R² is independently selected from the group consisting of hydrogen,halogen, optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆alkenyl, optionally substituted C₂₋₆ alkynyl, —CN, —OR⁵, —NR⁶R⁷, and—C(O)R⁸,

or both R² together with the carbon atoms to which they are attachedform a fused ring selected from the group consisting of C₃₋₇ carbocyclyland 3-7 membered heterocyclyl, each optionally substituted with one ormore R⁴;

R³ is selected from the group consisting of —(CH₂)_(n)—(C₆₋₁₀ aryl),—(CH₂)_(n)-(5-10 membered heteroaryl), —(CH₂)_(n)—(C₃₋₁₀ carbocyclyl),and —(CH₂)_(n)-(3-10 membered heterocyclyl), each optionally substitutedwith one or more R⁹;

each R⁴ is independently selected from the group consisting of halogen,—CN, —OH, —C(O)R⁸, —SO₂R¹⁶, optionally substituted C₁₋₆ alkyl,optionally substituted C₂₋₆ alkenyl, optionally substituted C₂₋₆alkynyl, optionally substituted C₁₋₆ alkoxy, optionally substitutedC₆₋₁₀ aryl optionally substituted with one or more R¹¹, C₇₋₁₄ aralkyloptionally substituted with one or more R¹¹, 5-10 membered heteroaryloptionally substituted with one or more R¹¹, or independently twogeminal R⁴ together are oxo;

each R⁵ is independently selected from the group consisting of hydrogen,optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl,optionally substituted C₂₋₆ alkynyl, optionally substituted C₂₋₈alkoxyalkyl, C₆₋₁₀ aryl optionally substituted with one or more R¹¹,C₇₋₁₄ aralkyl optionally substituted with one or more R¹¹, and—(CH₂)_(n)-(3-10 membered heterocyclyl) optionally substituted with oneor more R¹⁰;

R⁶ is selected from the group consisting of hydrogen, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl, optionallysubstituted C₂₋₆ alkynyl, C₆₋₁₀ aryl optionally substituted with one ormore R¹¹, C₇₋₁₄ aralkyl optionally substituted with one or more R¹¹,(5-10 membered heteroaryl)alkyl optionally substituted with one or moreR¹¹, —C(O)R⁸, and —C(O)OR⁵;

R⁷ is selected from the group consisting of hydrogen, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl, optionallysubstituted C₂₋₆ alkynyl, C₆₋₁₀ aryl optionally substituted with one ormore R¹¹, C₇₋₁₄ aralkyl optionally substituted with one or more R¹¹,(5-10 membered heteroaryl)alkyl optionally substituted with one or moreR¹¹, —C(O)R⁸, and —C(O)OR⁵;

or R⁶ and R⁷ together with the nitrogen to which they are attached forman 3-10 membered heterocyclyl optionally substituted with one or moreR¹⁰;

each R⁸ is independently selected from the group consisting of hydrogen,optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl,optionally substituted C₂₋₆ alkynyl, C₆₋₁₀ aryl optionally substitutedwith one or more R¹¹, C₇₋₁₄ aralkyl optionally substituted with one ormore R¹¹, —NR¹²R¹³, and —OR⁵;

each R⁹ is independently selected from the group consisting of halogen,optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl,optionally substituted C₂₋₆ alkynyl, optionally substituted C₁₋₆alkylthio, optionally substituted C₂₋₈ alkoxyalkyl, optionallysubstituted C₃₋₁₀ carbocyclyl, optionally substituted C₆₋₁₀ aryl, —OR⁵,—NR¹⁴R¹⁵, —C(O)R⁸, —SO₂R¹⁶, and —NO₂;

each R¹⁰ is independently selected from the group consisting ofoptionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl,and optionally substituted C₂₋₆ alkynyl, or independently two geminalR¹⁰ together are oxo;

each R¹¹ is independently selected from the group consisting of halogen,—CN, optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆alkenyl, optionally substituted C₂₋₆ alkynyl, and optionally substitutedC₁₋₆ alkoxy;

each R¹² is independently selected from the group consisting ofhydrogen, optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆alkenyl, optionally substituted C₂₋₆ alkynyl, C₆₋₁₀ aryl optionallysubstituted with one or more R¹¹, and C₇₋₁₄ aralkyl optionallysubstituted with one or more R¹¹;

each R¹³ is independently selected from the group consisting ofhydrogen, optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆alkenyl, optionally substituted C₂₋₆ alkynyl, C₆₋₁₀ aryl optionallysubstituted with one or more R¹¹, and C₇₋₁₄ aralkyl optionallysubstituted with one or more R¹¹;

R¹⁴ is selected from the group consisting of hydrogen, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₆₋₁₀ aryl, and —C(O)R⁸;

R¹⁵ is selected from the group consisting of hydrogen, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₆₋₁₀ aryl, and —C(O)R⁸;

each R¹⁶ is independently selected from the group consisting ofoptionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl,optionally substituted C₂₋₆ alkynyl, C₆₋₁₀ aryl optionally substitutedwith one or more R¹¹, C₇₋₁₄ aralkyl optionally substituted with one ormore R¹¹, —NR¹²R¹³, and —OR⁵;

Z is selected from oxygen and sulfur; and

each n is independently an integer from 0 to 4.

Some embodiments disclosed herein relate to methods of treating afibrotic condition, comprising administering a therapeutically effectiveamount of a compound of any one of Formulae (I), (II), (III), (IV), (V),(VIa), (VIb), (VII), (VIII) and (IX), a compound selected from Table 1,a pharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition thereof to a subject in need thereof. In some suchembodiments, the method further comprises identifying the subject ashaving or at risk of having said fibrotic condition. In some suchembodiments, the fibrotic condition is selected from the groupconsisting of pulmonary fibrosis, dermal fibrosis, pancreatic fibrosis,liver fibrosis, and renal fibrosis. In some embodiment, the fibroticcondition is idiopathic pulmonary fibrosis. In some embodiments, thesubject receiving such method of treatment is a human.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of ordinary skillin the art. All patents, applications, published applications and otherpublications referenced herein are incorporated by reference in theirentirety unless stated otherwise. In the event that there are aplurality of definitions for a term herein, those in this sectionprevail unless stated otherwise. As used in the specification and theappended claims, the singular forms “a,” “an” and “the” include pluralreferents unless the context clearly dictates otherwise. Unlessotherwise indicated, conventional methods of mass spectroscopy, NMR,HPLC, protein chemistry, biochemistry, recombinant DNA techniques andpharmacology are employed. The use of “or” or “and” means “and/or”unless stated otherwise. Furthermore, use of the term “including” aswell as other forms, such as “include”, “includes,” and “included,” isnot limiting. As used in this specification, whether in a transitionalphrase or in the body of the claim, the terms “comprise(s)” and“comprising” are to be interpreted as having an open-ended meaning. Thatis, the terms are to be interpreted synonymously with the phrases“having at least” or “including at least.” When used in the context of aprocess, the term “comprising” means that the process includes at leastthe recited steps, but may include additional steps. When used in thecontext of a compound, composition, or device, the term “comprising”means that the compound, composition, or device includes at least therecited features or components, but may also include additional featuresor components.

The section headings used herein are for organizational purposes onlyand are not to be construed as limiting the subject matter described.

As used herein, common organic abbreviations are defined as follows:

-   -   Ac Acetyl    -   Ac₂O Acetic anhydride    -   aq. Aqueous    -   Bn Benzyl    -   Bz Benzoyl    -   BOC or Boc tert-Butoxycarbonyl    -   Bu n-Butyl    -   cat. Catalytic    -   Cbz Carbobenzyloxy    -   CDI 1,1′-carbonyldiimidazole    -   ° C. Temperature in degrees Centigrade    -   DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene    -   DCE 1,2-Dichloroethane    -   DCM Methylene chloride    -   DIEA Diisopropylethylamine    -   DMA Dimethylacetamide    -   DME Dimethoxyethane    -   DMF N,N′-Dimethylformamide    -   DMSO Dimethylsulfoxide    -   DPPA Diphenylphosphoryl azide    -   ee % Enantiomeric excess    -   Et Ethyl    -   EtOAc or EA Ethyl acetate    -   g Gram(s)    -   h or hr Hour(s)    -   HATU 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium        hexafluorophosphate    -   HOBT N-Hydroxybenzotriazole    -   iPr Isopropyl    -   LCMS Liquid chromatography-mass spectrometry    -   LDA Lithium diisopropylamide    -   LiHMDS Lithium bis(trimethylsilyl)amide    -   m or min Minute(s)    -   mCPBA meta-Chloroperoxybenzoic Acid    -   MeOH Methanol    -   MeCN Acetonitrile    -   mL Milliliter(s)    -   MTBE Methyl tertiary-butyl ether    -   NH₄OAc Ammonium acetate    -   PE Petroleum ether    -   PG Protecting group    -   Pd/C Palladium on activated carbon    -   Pd(dppf)Cl₂,        1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride    -   Ph Phenyl    -   ppt Precipitate    -   PMBC 4-Methoxybenzyl chloride    -   RCM Ring closing metathesis    -   rt Room temperature    -   sBuLi sec-Butylithium    -   SFC Supercritical fluid chromatography    -   TBAF Tetrabutylammonium fluoride    -   TEA Triethylamine    -   TCDI 1,1′-Thiocarbonyl diimidazole    -   Tert, t tertiary    -   TFA Trifluoroacetic acid    -   TFAA Trifluoroacetic acid anhydride    -   THF Tetrahydrofuran    -   TLC Thin-layer chromatography    -   TMEDA Tetramethylethylenediamine    -   TMSNCO trimethylsilyl isocyanate    -   μL Microliter(s)

“Solvate” refers to the compound formed by the interaction of a solventand a compound described herein or salt thereof. Suitable solvates arepharmaceutically acceptable solvates including hydrates.

The term “pharmaceutically acceptable salt” refers to salts that retainthe biological effectiveness and properties of a compound and, which arenot biologically or otherwise undesirable for use in a pharmaceutical.In many cases, the compounds disclosed herein are capable of formingacid and/or base salts by virtue of the presence of amino and/orcarboxyl groups or groups similar thereto. Pharmaceutically acceptableacid addition salts can be formed with inorganic acids and organicacids. Inorganic acids from which salts can be derived include, forexample, hydrochloric acid, hydrobromic acid, sulfuric acid, nitricacid, phosphoric acid, and the like. Organic acids from which salts canbe derived include, for example, acetic acid, propionic acid, glycolicacid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinicacid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamicacid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceuticallyacceptable base addition salts can be formed with inorganic and organicbases. Inorganic bases from which salts can be derived include, forexample, sodium, potassium, lithium, ammonium, calcium, magnesium, iron,zinc, copper, manganese, aluminum, and the like; particularly preferredare the ammonium, potassium, sodium, calcium and magnesium salts.Organic bases from which salts can be derived include, for example,primary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines, basic ionexchange resins, and the like, specifically such as isopropylamine,trimethylamine, diethylamine, triethylamine, tripropylamine, andethanolamine. Many such salts are known in the art, as described in WO87/05297, Johnston et al., published Sep. 11, 1987 (incorporated byreference herein in its entirety).

As used herein, “C_(a) to C_(b)” or “C_(a-b)” in which “a” and “b” areintegers refer to the number of carbon atoms in the specified group.That is, the group can contain from “a” to “b”, inclusive, carbon atoms.Thus, for example, a “C₁ to C₄ alkyl” or “C₁₋₄ alkyl” group refers toall alkyl groups having from 1 to 4 carbons, that is, CH₃—, CH₃CH₂—,CH₃CH₂CH₂—, (CH₃)₂CH—, CH₃CH₂CH₂CH₂—, CH₃CH₂CH(CH₃)— and (CH₃)₃C—.

The term “halogen” or “halo,” as used herein, means any one of theradio-stable atoms of column 7 of the Periodic Table of the Elements,e.g., fluorine, chlorine, bromine, or iodine, with fluorine and chlorinebeing preferred.

As used herein, “alkyl” refers to a straight or branched hydrocarbonchain that is fully saturated (i.e., contains no double or triplebonds). The alkyl group may have 1 to 20 carbon atoms (whenever itappears herein, a numerical range such as “1 to 20” refers to eachinteger in the given range; e.g., “1 to 20 carbon atoms” means that thealkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbonatoms, etc., up to and including 20 carbon atoms, although the presentdefinition also covers the occurrence of the term “alkyl” where nonumerical range is designated). The alkyl group may also be a mediumsize alkyl having 1 to 9 carbon atoms. The alkyl group could also be alower alkyl having 1 to 4 carbon atoms. The alkyl group may bedesignated as “C₁₋₄ alkyl” or similar designations. By way of exampleonly, “C₁₋₄ alkyl” indicates that there are one to four carbon atoms inthe alkyl chain, i.e., the alkyl chain is selected from the groupconsisting of methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl,sec-butyl, and t-butyl. Typical alkyl groups include, but are in no waylimited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiarybutyl, pentyl, hexyl, and the like.

As used herein, “alkoxy” refers to the formula —OR wherein R is an alkylas is defined above, such as “C₁₋₉ alkoxy”, including but not limited tomethoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy,iso-butoxy, sec-butoxy, and tert-butoxy, and the like.

As used herein, “alkylthio” refers to the formula —SR wherein R is analkyl as is defined above, such as “C₁₋₉ alkylthio” and the like,including but not limited to methylmercapto, ethylmercapto,n-propylmercapto, 1-methylethylmercapto (isopropylmercapto),n-butylmercapto, iso-butylmercapto, sec-butylmercapto,tert-butylmercapto, and the like.

As used herein, “alkenyl” refers to a straight or branched hydrocarbonchain containing one or more double bonds. The alkenyl group may have 2to 20 carbon atoms, although the present definition also covers theoccurrence of the term “alkenyl” where no numerical range is designated.The alkenyl group may also be a medium size alkenyl having 2 to 9 carbonatoms. The alkenyl group could also be a lower alkenyl having 2 to 4carbon atoms. The alkenyl group may be designated as “C₂₋₄ alkenyl” orsimilar designations. By way of example only, “C₂₋₄ alkenyl” indicatesthat there are two to four carbon atoms in the alkenyl chain, i.e., thealkenyl chain is selected from the group consisting of ethenyl,propen-1-yl, propen-2-yl, propen-3-yl, buten-1-yl, buten-2-yl,buten-3-yl, buten-4-yl, 1-methyl-propen-1-yl, 2-methyl-propen-1-yl,1-ethyl-ethen-1-yl, 2-methyl-propen-3-yl, buta-1,3-dienyl,buta-1,2,-dienyl, and buta-1,2-dien-4-yl. Typical alkenyl groupsinclude, but are in no way limited to, ethenyl, propenyl, butenyl,pentenyl, and hexenyl, and the like.

As used herein, “alkynyl” refers to a straight or branched hydrocarbonchain containing one or more triple bonds. The alkynyl group may have 2to 20 carbon atoms, although the present definition also covers theoccurrence of the term “alkynyl” where no numerical range is designated.The alkynyl group may also be a medium size alkynyl having 2 to 9 carbonatoms. The alkynyl group could also be a lower alkynyl having 2 to 4carbon atoms. The alkynyl group may be designated as “C₂₋₄ alkynyl” orsimilar designations. By way of example only, “C₂₋₄ alkynyl” indicatesthat there are two to four carbon atoms in the alkynyl chain, i.e., thealkynyl chain is selected from the group consisting of ethynyl,propyn-1-yl, propyn-2-yl, butyn-1-yl, butyn-3-yl, butyn-4-yl, and2-butynyl. Typical alkynyl groups include, but are in no way limited to,ethynyl, propynyl, butynyl, pentynyl, and hexynyl, and the like.

As used herein, “heteroalkyl” refers to a straight or branchedhydrocarbon chain containing one or more heteroatoms, that is, anelement other than carbon, including but not limited to, nitrogen,oxygen and sulfur, in the chain backbone. The heteroalkyl group may have1 to 20 carbon atom, although the present definition also covers theoccurrence of the term “heteroalkyl” where no numerical range isdesignated. The heteroalkyl group may also be a medium size heteroalkylhaving 1 to 9 carbon atoms. The heteroalkyl group could also be a lowerheteroalkyl having 1 to 4 carbon atoms. The heteroalkyl group may bedesignated as “C₁₋₄ heteroalkyl” or similar designations. Theheteroalkyl group may contain one or more heteroatoms. By way of exampleonly, “C₁₋₄ heteroalkyl” indicates that there are one to four carbonatoms in the heteroalkyl chain and additionally one or more heteroatomsin the backbone of the chain.

As used herein, “alkylene” means a branched, or straight chain fullysaturated di-radical chemical group containing only carbon and hydrogenthat is attached to the rest of the molecule via two points ofattachment (i.e., an alkanediyl). The alkylene group may have 1 to 20carbon atoms, although the present definition also covers the occurrenceof the term alkylene where no numerical range is designated. Thealkylene group may also be a medium size alkylene having 1 to 9 carbonatoms. The alkylene group could also be a lower alkylene having 1 to 4carbon atoms. The alkylene group may be designated as “C₁₋₄ alkylene” orsimilar designations. By way of example only, “C₁₋₄ alkylene” indicatesthat there are one to four carbon atoms in the alkylene chain, i.e., thealkylene chain is selected from the group consisting of methylene,ethylene, ethan-1,1-diyl, propylene, propan-1,1-diyl, propan-2,2-diyl,1-methyl-ethylene, butylene, butan-1,1-diyl, butan-2,2-diyl,2-methyl-propan-1,1-diyl, 1-methyl-propylene, 2-methyl-propylene,1,1-dimethyl-ethylene, 1,2-dimethyl-ethylene, and 1-ethyl-ethylene.

As used herein, “alkenylene” means a straight or branched chaindi-radical chemical group containing only carbon and hydrogen andcontaining at least one carbon-carbon double bond that is attached tothe rest of the molecule via two points of attachment. The alkenylenegroup may have 2 to 20 carbon atoms, although the present definitionalso covers the occurrence of the term alkenylene where no numericalrange is designated. The alkenylene group may also be a medium sizealkenylene having 2 to 9 carbon atoms. The alkenylene group could alsobe a lower alkenylene having 2 to 4 carbon atoms. The alkenylene groupmay be designated as “C₂₋₄ alkenylene” or similar designations. By wayof example only, “C₂₋₄ alkenylene” indicates that there are two to fourcarbon atoms in the alkenylene chain, i.e., the alkenylene chain isselected from the group consisting of ethenylene, ethen-1,1-diyl,propenylene, propen-1,1-diyl, prop-2-en-1,1-diyl, 1-methyl-ethenylene,but-1-enylene, but-2-enylene, but-1,3-dienylene, buten-1,1-diyl,but-1,3-dien-1,1-diyl, but-2-en-1,1-diyl, but-3-en-1,1-diyl,1-methyl-prop-2-en-1,1-diyl, 2-methyl-prop-2-en-1,1-diyl,1-ethyl-ethenylene, 1,2-dimethyl-ethenylene, 1-methyl-propenylene,2-methyl-propenylene, 3-methyl-propenylene, 2-methyl-propen-1,1-diyl,and 2,2-dimethyl-ethen-1,1-diyl.

The term “aromatic” refers to a ring or ring system having a conjugatedpi electron system and includes both carbocyclic aromatic (e.g., phenyl)and heterocyclic aromatic groups (e.g., pyridine). The term includesmonocyclic or fused-ring polycyclic (i.e., rings which share adjacentpairs of atoms) groups provided that the entire ring system is aromatic.

As used herein, “aryl” refers to an aromatic ring or ring system (i.e.,two or more fused rings that share two adjacent carbon atoms) containingonly carbon in the ring backbone. When the aryl is a ring system, everyring in the system is aromatic. The aryl group may have 6 to 18 carbonatoms, although the present definition also covers the occurrence of theterm “aryl” where no numerical range is designated. In some embodiments,the aryl group has 6 to 10 carbon atoms. The aryl group may bedesignated as “C₆₋₁₀ aryl,” “C₆ or C₁₀ aryl,” or similar designations.Examples of aryl groups include, but are not limited to, phenyl,naphthyl, azulenyl, and anthracenyl.

As used herein, “aryloxy” and “arylthio” refers to RO— and RS—, in whichR is an aryl as is defined above, such as “C₆₋₁₀ aryloxy” or “C₆₋₁₀arylthio” and the like, including but not limited to phenyloxy.

An “aralkyl” or “arylalkyl” is an aryl group connected, as asubstituent, via an alkylene group, such as “C₇₋₁₄ aralkyl” and thelike, including but not limited to benzyl, 2-phenylethyl,3-phenylpropyl, and naphthylalkyl. In some cases, the alkylene group isa lower alkylene group (i.e., a C₁₋₄ alkylene group).

As used herein, “heteroaryl” refers to an aromatic ring or ring system(i.e., two or more fused rings that share two adjacent atoms) thatcontain(s) one or more heteroatoms, that is, an element other thancarbon, including but not limited to, nitrogen, oxygen and sulfur, inthe ring backbone. When the heteroaryl is a ring system, every ring inthe system is aromatic. The heteroaryl group may have 5-18 ring members(i.e., the number of atoms making up the ring backbone, including carbonatoms and heteroatoms), although the present definition also covers theoccurrence of the term “heteroaryl” where no numerical range isdesignated. In some embodiments, the heteroaryl group has 5 to 10 ringmembers or 5 to 7 ring members. The heteroaryl group may be designatedas “5-7 membered heteroaryl,” “5-10 membered heteroaryl,” or similardesignations. Examples of heteroaryl rings include, but are not limitedto, furyl, thienyl, phthalazinyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl,thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl,quinolinyl, isoquinlinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl,indolyl, isoindolyl, and benzothienyl.

A “heteroaralkyl” or “heteroarylalkyl” is heteroaryl group connected, asa substituent, via an alkylene group. Examples include but are notlimited to 2-thienylmethyl, 3-thienylmethyl, furylmethyl, thienylethyl,pyrrolylalkyl, pyridylalkyl, isoxazollylalkyl, and imidazolylalkyl. Insome cases, the alkylene group is a lower alkylene group (i.e., a C₁₋₄alkylene group).

As used herein, “carbocyclyl” means a non-aromatic cyclic ring or ringsystem containing only carbon atoms in the ring system backbone. Whenthe carbocyclyl is a ring system, two or more rings may be joinedtogether in a fused, bridged or spiro-connected fashion. Carbocyclylsmay have any degree of saturation provided that at least one ring in aring system is not aromatic. Thus, carbocyclyls include cycloalkyls,cycloalkenyls, and cycloalkynyls. The carbocyclyl group may have 3 to 20carbon atoms, although the present definition also covers the occurrenceof the term “carbocyclyl” where no numerical range is designated. Thecarbocyclyl group may also be a medium size carbocyclyl having 3 to 10carbon atoms. The carbocyclyl group could also be a carbocyclyl having 3to 6 carbon atoms. The carbocyclyl group may be designated as “C₃₋₆carbocyclyl” or similar designations. Examples of carbocyclyl ringsinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cyclohexenyl, 2,3-dihydro-indene, bicycle[2.2.2]octanyl,adamantyl, and spiro[4.4]nonanyl.

A “(carbocyclyl)alkyl” is a carbocyclyl group connected, as asubstituent, via an alkylene group, such as “C₄₋₁₀ (carbocyclyl)alkyl”and the like, including but not limited to, cyclopropylmethyl,cyclobutylmethyl, cyclopropylethyl, cyclopropylbutyl, cyclobutylethyl,cyclopropylisopropyl, cyclopentylmethyl, cyclopentylethyl,cyclohexylmethyl, cyclohexylethyl, cycloheptylmethyl, and the like. Insome cases, the alkylene group is a lower alkylene group.

As used herein, “cycloalkyl” means a fully saturated carbocyclyl ring orring system. Examples include cyclopropyl, cyclobutyl, cyclopentyl, andcyclohexyl.

As used herein, “cycloalkenyl” means a carbocyclyl ring or ring systemhaving at least one double bond, wherein no ring in the ring system isaromatic. An example is cyclohexenyl.

As used herein, “heterocyclyl” means a non-aromatic cyclic ring or ringsystem containing at least one heteroatom in the ring backbone.Heterocyclyls may be joined together in a fused, bridged orspiro-connected fashion. Heterocyclyls may have any degree of saturationprovided that at least one ring in the ring system is not aromatic. Theheteroatom(s) may be present in either a non-aromatic or aromatic ringin the ring system. The heterocyclyl group may have 3 to 20 ring members(i.e., the number of atoms making up the ring backbone, including carbonatoms and heteroatoms), although the present definition also covers theoccurrence of the term “heterocyclyl” where no numerical range isdesignated. The heterocyclyl group may also be a medium sizeheterocyclyl having 3 to 10 ring members. The heterocyclyl group couldalso be a heterocyclyl having 3 to 6 ring members. The heterocyclylgroup may be designated as “3-6 membered heterocyclyl” or similardesignations. In preferred six membered monocyclic heterocyclyls, theheteroatom(s) are selected from one up to three of 0, N or S, and inpreferred five membered monocyclic heterocyclyls, the heteroatom(s) areselected from one or two heteroatoms selected from O, N, or S. Examplesof heterocyclyl rings include, but are not limited to, azepinyl,acridinyl, carbazolyl, cinnolinyl, dioxolanyl, imidazolinyl,imidazolidinyl, morpholinyl, oxiranyl, oxepanyl, thiepanyl, piperidinyl,piperazinyl, dioxopiperazinyl, pyrrolidinyl, pyrrolidonyl,pyrrolidionyl, 4-piperidonyl, pyrazolinyl, pyrazolidinyl, 1,3-dioxinyl,1,3-dioxanyl, 1,4-dioxinyl, 1,4-dioxanyl, 1,3-oxathianyl,1,4-oxathiinyl, 1,4-oxathianyl, 2H-1,2-oxazinyl, trioxanyl,hexahydro-1,3,5-triazinyl, 1,3-dioxolyl, 1,3-dioxolanyl, 1,3-dithiolyl,1,3-dithiolanyl, isoxazolinyl, isoxazolidinyl, oxazolinyl, oxazolidinyl,oxazolidinonyl, thiazolinyl, thiazolidinyl, 1,3-oxathiolanyl, indolinyl,isoindolinyl, tetrahydrofuranyl, tetrahydropyranyl,tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydro-1,4-thiazinyl,thiamorpholinyl, dihydrobenzofuranyl, benzimidazolidinyl, andtetrahydroquinoline.

A “(heterocyclyl)alkyl” is a heterocyclyl group connected, as asubstituent, via an alkylene group. Examples include, but are notlimited to, imidazolinylmethyl and indolinylethyl.

As used herein, “acyl” refers to —C(═O)R, wherein R is hydrogen, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ carbocyclyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.Non-limiting examples include formyl, acetyl, propanoyl, benzoyl, andacryl.

An “O-carboxy” group refers to a “—OC(═O)R” group in which R is selectedfrom hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ carbocyclyl,C₆₋₁₀ aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, asdefined herein.

A “C-carboxy” group refers to a “—C(═O)OR” group in which R is selectedfrom hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ carbocyclyl,C₆₋₁₀ aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, asdefined herein. A non-limiting example includes carboxyl (i.e.,—C(═O)OH).

A “cyano” group refers to a “—CN” group.

A “cyanato” group refers to an “—OCN” group.

An “isocyanato” group refers to a “—NCO” group.

A “thiocyanato” group refers to a “—SCN” group.

An “isothiocyanato” group refers to an “—NCS” group.

A “sulfinyl” group refers to an “—S(═O)R” group in which R is selectedfrom hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ carbocyclyl,C₆₋₁₀ aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, asdefined herein.

A “sulfonyl” group refers to an “—SO₂R” group in which R is selectedfrom hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ carbocyclyl,C₆₋₁₀ aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, asdefined herein.

An “S-sulfonamido” group refers to a “—SO₂NR_(A)R_(B)” group in whichR_(A) and R_(B) are each independently selected from hydrogen, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ carbocyclyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.

An “N-sulfonamido” group refers to a “—N(R_(A))SO₂R_(B)” group in whichR_(A) and R_(B) are each independently selected from hydrogen, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ carbocyclyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.

An “O-carbamyl” group refers to a “—OC(═O)NR_(A)R_(B)” group in whichR_(A) and R_(B) are each independently selected from hydrogen, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ carbocyclyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.

An “N-carbamyl” group refers to an “—N(R_(A))OC(═O)R_(B)” group in whichR_(A) and R_(B) are each independently selected from hydrogen, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ carbocyclyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.

An “O-thiocarbamyl” group refers to a “—OC(═S)NR_(A)R_(B)” group inwhich R_(A) and R_(B) are each independently selected from hydrogen,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ carbocyclyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as definedherein.

An “N-thiocarbamyl” group refers to an “—N(R_(A))OC(═S)R_(B)” group inwhich R_(A) and R_(B) are each independently selected from hydrogen,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ carbocyclyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as definedherein.

A “C-amido” group refers to a “—C(═O)NR_(A)R_(B)” group in which R_(A)and R_(B) are each independently selected from hydrogen, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ carbocyclyl, C₆₋₁₀ aryl, 5-10 memberedheteroaryl, and 5-10 membered heterocyclyl, as defined herein.

An “N-amido” group refers to a “—N(R_(A))C(═O)R_(B)” group in whichR_(A) and R_(B) are each independently selected from hydrogen, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ carbocyclyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.

An “amino” group refers to a “—NR_(A)R_(B)” group in which R_(A) andR_(B) are each independently selected from hydrogen, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₇ carbocyclyl, C₆₋₁₀ aryl, 5-10 memberedheteroaryl, and 5-10 membered heterocyclyl, as defined herein. Anon-limiting example includes free amino (i.e., —NH₂).

An “aminoalkyl” group refers to an amino group connected via an alkylenegroup.

An “alkoxyalkyl” group refers to an alkoxy group connected via analkylene group, such as a “C₂₋₈ alkoxyalkyl” and the like.

As used herein, a substituted group is derived from the unsubstitutedparent group in which there has been an exchange of one or more hydrogenatoms for another atom or group. Unless otherwise indicated, when agroup is deemed to be “substituted,” it is meant that the group issubstituted with one or more substituents independently selected fromC₁-C₆ alkyl, C₁-C₆ alkenyl, C₁-C₆ alkynyl, C₁-C₆ heteroalkyl, C₃-C₇carbocyclyl (optionally substituted with halo, C₁-C₆ alkyl, C₁-C₆alkoxy, C₁-C₆ haloalkyl, and C₁-C₆ haloalkoxy),C₃-C₇-carbocyclyl-C₁-C₆-alkyl (optionally substituted with halo, C₁-C₆alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, and C₁-C₆ haloalkoxy), 5-10membered heterocyclyl (optionally substituted with halo, C₁-C₆ alkyl,C₁-C₆ alkoxy, C₁-C₆ haloalkyl, and C₁-C₆ haloalkoxy), 5-10 memberedheterocyclyl-C₁-C₆-alkyl (optionally substituted with halo, C₁-C₆ alkyl,C₁-C₆ alkoxy, C₁-C₆ haloalkyl, and C₁-C₆ haloalkoxy), aryl (optionallysubstituted with halo, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, andC₁-C₆ haloalkoxy), aryl(C₁-C₆)alkyl (optionally substituted with halo,C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, and C₁-C₆ haloalkoxy), 5-10membered heteroaryl (optionally substituted with halo, C₁-C₆ alkyl,C₁-C₆ alkoxy, C₁-C₆ haloalkyl, and C₁-C₆ haloalkoxy), 5-10 memberedheteroaryl(C₁-C₆)alkyl (optionally substituted with halo, C₁-C₆ alkyl,C₁-C₆ alkoxy, C₁-C₆ haloalkyl, and C₁-C₆ haloalkoxy), halo, cyano,hydroxy, C₁-C₆ alkoxy, C₁-C₆ alkoxy(C₁-C₆)alkyl (i.e., ether), aryloxy,sulfhydryl (mercapto), halo(C₁-C₆)alkyl (e.g., —CF₃), halo(C₁-C₆)alkoxy(e.g., —OCF₃), C₁-C₆ alkylthio, arylthio, amino, amino(C₁-C₆)alkyl,nitro, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido,N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, acyl,cyanato, isocyanato, thiocyanato, isothiocyanato, sulfinyl, sulfonyl,and oxo (═O). Wherever a group is described as “optionally substituted”that group can be substituted with the above substituents.

It is to be understood that certain radical naming conventions caninclude either a mono-radical or a di-radical, depending on the context.For example, where a substituent requires two points of attachment tothe rest of the molecule, it is understood that the substituent is adi-radical. For example, a substituent identified as alkyl that requirestwo points of attachment includes di-radicals such as —CH₂—, —CH₂CH₂—,—CH₂CH(CH₃)CH₂—, and the like. Other radical naming conventions clearlyindicate that the radical is a di-radical such as “alkylene” or“alkenylene.”

When two R groups are said to form a ring (e.g., a carbocyclyl,heterocyclyl, aryl, or heteroaryl ring) “together with the atom to whichthey are attached,” it is meant that the collective unit of the atom andthe two R groups are the recited ring. The ring is not otherwise limitedby the definition of each R group when taken individually. For example,when the following substructure is present:

and R¹ and R² are defined as selected from the group consisting ofhydrogen and alkyl, or R¹ and R² together with the nitrogen to whichthey are attached form a heterocyclyl, it is meant that R¹ and R² can beselected from hydrogen or alkyl, or alternatively, the substructure hasstructure:

where ring A is a heteroaryl ring containing the depicted nitrogen.

Similarly, when two “adjacent” R groups are said to form a ring“together with the atom to which they are attached,” it is meant thatthe collective unit of the atoms, intervening bonds, and the two Rgroups are the recited ring. For example, when the followingsubstructure is present:

and R¹ and R² are defined as selected from the group consisting ofhydrogen and alkyl, or R¹ and R² together with the atoms to which theyare attached form an aryl or carbocylyl, it is meant that R¹ and R² canbe selected from hydrogen or alkyl, or alternatively, the substructurehas structure:

where A is an aryl ring or a carbocylyl containing the depicted doublebond.

Wherever a substituent is depicted as a di-radical (i.e., has two pointsof attachment to the rest of the molecule), it is to be understood thatthe substituent can be attached in any directional configuration unlessotherwise indicated. Thus, for example, a substituent depicted as -AE-or

includes the substituent being oriented such that the A is attached atthe leftmost attachment point of the molecule as well as the case inwhich A is attached at the rightmost attachment point of the molecule.

As used herein, “isosteres” of a chemical group are other chemicalgroups that exhibit the same or similar properties. For example,tetrazole is an isostere of carboxylic acid because it mimics theproperties of carboxylic acid even though they both have very differentmolecular formulae. Tetrazole is one of many possible isostericreplacements for carboxylic acid. Other carboxylic acid isosterescontemplated include —SO₃H, —SO₂HNR, —PO₂(R)₂, —PO₃(R)₂, —CONHNHSO₂R,—COHNSO₂R, and —CONRCN, where R is selected from hydrogen, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ carbocyclyl, C₆₋₁₀ aryl, 5-10 memberedheteroaryl, and 5-10 membered heterocyclyl, as defined herein. Inaddition, carboxylic acid isosteres can include 5-7 membered carbocyclesor heterocycles containing any combination of CH₂, O, S, or N in anychemically stable oxidation state, where any of the atoms of said ringstructure are optionally substituted in one or more positions. Thefollowing structures are non-limiting examples of carbocyclic andheterocyclic isosteres contemplated. The atoms of said ring structuremay be optionally substituted at one or more positions with R as definedabove.

It is also contemplated that when chemical substituents are added to acarboxylic isostere, the compound retains the properties of a carboxylicisostere. It is contemplated that when a carboxylic isostere isoptionally substituted with one or more moieties selected from R asdefined above, then the substitution and substitution position isselected such that it does not eliminate the carboxylic acid isostericproperties of the compound. Similarly, it is also contemplated that theplacement of one or more R substituents upon a carbocyclic orheterocyclic carboxylic acid isostere is not a substitution at one ormore atom(s) that maintain(s) or is/are integral to the carboxylic acidisosteric properties of the compound, if such substituent(s) woulddestroy the carboxylic acid isosteric properties of the compound.

Other carboxylic acid isosteres not specifically exemplified in thisspecification are also contemplated.

“Subject” as used herein, means a human or a non-human mammal, e.g., adog, a cat, a mouse, a rat, a cow, a sheep, a pig, a goat, a non-humanprimate or a bird, e.g., a chicken, as well as any other vertebrate orinvertebrate.

The term “mammal” is used in its usual biological sense. Thus, itspecifically includes, but is not limited to, primates, includingsimians (chimpanzees, apes, monkeys) and humans, cattle, horses, sheep,goats, swine, rabbits, dogs, cats, rodents, rats, mice guinea pigs, orthe like.

The term “pharmaceutically acceptable carrier” or “pharmaceuticallyacceptable excipient” includes any and all solvents, dispersion media,coatings, antibacterial and antifungal agents, isotonic and absorptiondelaying agents and the like. The use of such media and agents forpharmaceutically active substances is well known in the art. Exceptinsofar as any conventional media or agent is incompatible with theactive ingredient, its use in the therapeutic compositions iscontemplated. In addition, various adjuvants such as are commonly usedin the art may be included. Considerations for the inclusion of variouscomponents in pharmaceutical compositions are described, e.g., in Gilmanet al. (Eds.) (1990); Goodman and Gilman's: The Pharmacological Basis ofTherapeutics, 8th Ed., Pergamon Press.

A therapeutic effect relieves, to some extent, one or more of thesymptoms of a disease or condition, and includes curing a disease orcondition. “Curing” means that the symptoms of a disease or conditionare eliminated; however, certain long-term or permanent effects mayexist even after a cure is obtained (such as extensive tissue damage).

“Treat,” “treatment,” or “treating,” as used herein refers toadministering a compound or pharmaceutical composition to a subject forprophylactic and/or therapeutic purposes. The term “prophylactictreatment” refers to treating a subject who does not yet exhibitsymptoms of a disease or condition, but who is susceptible to, orotherwise at risk of, a particular disease or condition, whereby thetreatment reduces the likelihood that the patient will develop thedisease or condition. The term “therapeutic treatment” refers toadministering treatment to a subject already suffering from a disease orcondition.

Where the compounds disclosed herein have at least one chiral center,they may exist as individual enantiomers and diastereomers or asmixtures of such isomers, including racemates. Separation of theindividual isomers or selective synthesis of the individual isomers isaccomplished by application of various methods which are well known topractitioners in the art. Unless otherwise indicated, all such isomersand mixtures thereof are included in the scope of the compoundsdisclosed herein. Furthermore, compounds disclosed herein may exist inone or more crystalline or amorphous forms. Unless otherwise indicated,all such forms are included in the scope of the compounds disclosedherein including any polymorphic forms. In addition, some of thecompounds disclosed herein may form solvates with water (i.e., hydrates)or common organic solvents. Unless otherwise indicated, such solvatesare included in the scope of the compounds disclosed herein.

The skilled artisan will recognize that some structures described hereinmay be resonance forms or tautomers of compounds that may be fairlyrepresented by other chemical structures, even when kinetically; theartisan recognizes that such structures may only represent a very smallportion of a sample of such compound(s). Such compounds are consideredwithin the scope of the structures depicted, though such resonance formsor tautomers are not represented herein.

Isotopes may be present in the compounds described. Each chemicalelement as represented in a compound structure may include any isotopeof said element. For example, in a compound structure a hydrogen atommay be explicitly disclosed or understood to be present in the compound.At any position of the compound that a hydrogen atom may be present, thehydrogen atom can be any isotope of hydrogen, including but not limitedto hydrogen-1 (protium) and hydrogen-2 (deuterium). Thus, referenceherein to a compound encompasses all potential isotopic forms unless thecontext clearly dictates otherwise.

Compounds

Formula I

Some embodiments disclosed herein relate to a compound of formula (I) asdescribed above or a pharmaceutically acceptable salt thereof.

Some embodiments disclosed herein with respect to the compounds offormula (I), R² is selected from the group consisting of halogen, —OR⁵,—NR⁶R⁷, and —C(O)R⁸; R³ is selected from the group consisting of—(CH₂)_(n)—(C₆₋₁₀ aryl), —(CH₂)_(n)-(5-10 membered heteroaryl),—(CH₂)_(n)—(C₃₋₁₀ carbocyclyl), and —(CH₂)_(n)-(3-10 memberedheterocyclyl), each optionally substituted with one or more R⁹; each R⁹is independently selected from the group consisting of halogen,optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl,optionally substituted C₂₋₆ alkynyl, optionally substituted C₁₋₆alkylthio, optionally substituted C₂₋₈ alkoxyalkyl, optionallysubstituted C₃₋₁₀ carbocyclyl, optionally substituted C₆₋₁₀ aryl, —OR⁵,—NR¹⁴R¹⁵, —C(O)R⁸, —SO₂R¹⁶, and —NO₂; and each R¹¹ is independentlyselected from the group consisting of halogen, —CN, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl, optionallysubstituted C₂₋₆ alkynyl, and optionally substituted C₁₋₆ alkoxy.

In some embodiments, R¹ is a C₆₋₁₀ aryl optionally substituted with oneor more R⁴. In some further embodiments, R¹ is a phenyl optionallysubstituted with one or more R⁴.

In some embodiments, R¹ is a 5-10 membered heteroaryl optionallysubstituted with one or more R⁴. In some such embodiments, R¹ is apyrazolyl or 1-methyl pyrazolyl optionally substituted with one or moreR⁴. In some such embodiments, R¹ is a pyridazinyl optionally substitutedwith one or more R⁴. In some such embodiments, R¹ is a pyrimidinyloptionally substituted with one or more R⁴.

In any of the embodiments of Formula (I) described herein, each R⁴ isindependently selected from halogen, or optionally substituted C₁₋₆alkyl. In some embodiments, R⁴ is halogen. In some embodiments, R⁴ issubstituted C₁₋₆ alkyl. In some other embodiments, R⁴ is unsubstitutedC₁₋₆ alkyl. In some embodiments, R⁴ is fluoro. In some otherembodiments, R⁴ is methyl.

In some embodiments, R² is halogen. In some further embodiments, R² isselected from bromo or chloro.

In some embodiments, R² is —CN.

In some embodiments, R² is —OR⁵. In some embodiments, R⁵ is selectedfrom hydrogen, optionally substituted C₁₋₆ alkyl, optionally substitutedC₂₋₈ alkoxyalkyl, C₇₋₁₄ aralkyl optionally substituted with one or moreR¹¹, C₆₋₁₀ aryl optionally substituted with one or more R¹¹, and—(CH₂)_(n)-(3-10 membered heterocyclyl) optionally substituted with oneor more R¹⁰. In some embodiments, R⁵ is hydrogen. In some embodiments,R⁵ is optionally substituted C₁₋₆ alkyl. In some such embodiments, R⁵ ismethyl. In some such embodiments, R⁵ is halogen substituted ethyl. Insome embodiments, R⁵ is C₆₋₁₀ aryl optionally substituted with one ormore R¹¹. In some such embodiments, R⁵ is phenyl optionally substitutedwith one or more R¹¹. In some such embodiments, R⁵ is unsubstitutedphenyl. In some embodiments, R⁵ is C₇₋₁₄ aralkyl optionally substitutedwith one or more R¹¹. In some such embodiments, R⁵ is benzyl optionallysubstituted with one or more R¹¹. In some such embodiments, R⁵ isunsubstituted benzy. In some such embodiments, R⁵ is optionallysubstituted C₂₋₈ alkoxyalkyl. In some such embodiments, R⁵ is selectedfrom —(CH₂)₂OCH₃, —(CH₂)₂OC₃H₇ or —(CH₂)₂O(CH₂)OCH₃. In some suchembodiments, R⁵ is —(CH₂)_(n)-(5 or 6 membered heterocyclyl) optionallysubstituted with one or more R¹⁰. In some such embodiments, R⁵ is

optionally substituted with one or more R¹⁰. In some such embodiments,R⁵ is selected from

each optionally substituted with one or more R¹⁰. In some embodiments,R⁵ can be optionally substituted

In some embodiments, R⁵ can be optionally substituted

In some embodiments, R⁵ can be optionally substituted

In some embodiments, R⁵ can be optionally substituted

In some embodiments, R⁵ can be optionally substituted

In some embodiments, R⁵ can be optionally substituted

In some embodiments, R⁵ can be optionally substituted

In some embodiments of this paragraph, n is 0. In some embodiments ofthis paragraph, n is 1. In some embodiments of this paragraph, R⁵ issubstituted with one or more substituents selected from C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ alkyl, —O(CH₂)₂OCH₃, halogen or —C(O)NH₂.

In some embodiments, R² is —NR⁶R⁷. In some embodiments, each R⁶ and R⁷is independently selected from hydrogen, C₁₋₆ alkyl, C₆₋₁₀ aryloptionally substituted with one or more R¹¹, C₇₋₁₄ aralkyl optionallysubstituted with one or more R¹¹, (5-10 membered heteroaryl)alkyloptionally substituted with one or more R¹¹, —C(O)R⁸, or —C(O)OR⁵. Insome embodiments, R⁶ is hydrogen. In some other embodiments, R⁶ is C₁₋₆alkyl. In some embodiments, R⁷ is hydrogen. In some embodiments, R⁷ isC₁₋₆ alkyl. In some embodiments, R⁷ is C₆₋₁₀ aryl optionally substitutedwith one or more R¹¹. In some embodiments, R⁷ is phenyl optionallysubstituted with one or more R¹¹. In some other embodiments, R⁷ isunsubstituted phenyl.

In some embodiments, R⁷ is C₇₋₁₄ aralkyl optionally substituted with oneor more R¹¹. In some embodiments, R⁷ is benzyl or —(CH₂)₂Ph, eachoptionally substituted with one or more R¹¹. In some such embodiments,R⁷ is substituted with one or more substituents selected from C₁₋₆alkyl, C₁₋₆ alkoxy, C₁₋₆ alkyl, —O(CH₂)₂OCH₃, halogen or —CN. In someembodiments, R⁷ is unsubstituted benzyl. In some other embodiments, R⁷is unsubstituted —(CH₂)₂Ph.

In some embodiments, R⁷ is (6 membered heteroaryl)alkyl optionallysubstituted with one or more R¹¹. In some embodiments, R⁷ is—CH₂-pyridyl, —CH₂-pyrimidinyl or —CH₂— pyrazinyl, each optionallysubstituted with one or more R¹¹. In some embodiments, R⁷ isunsubstituted —CH₂-pyridyl. In some embodiments, R⁷ is unsubstituted—CH₂-pyrazinyl. In some embodiments, R⁷ is unsubstituted—CH₂-pyrimidinyl.

In some embodiments, R⁷ is —C(O)R⁸. In some embodiments, R⁸ is selectedfrom C₁₋₆ alkyl, C₆₋₁₀ aryl, or —NR¹²R¹³. In some embodiments, R⁸ isselected from methyl, ethyl, propyl, isopropyl, butyl, pentyl or phenyl.In some embodiments, R⁸ is methyl. In some other embodiments, R⁸ isphenyl. In some embodiments, R⁸ is —NR¹²R¹³. In some embodiments, eachR¹² and R¹³ is independently selected from hydrogen, C₁₋₆ alkyl, orbenzyl.

In some embodiments, R⁷ is —C(O)OR⁵. In some embodiments, R⁵ is selectedfrom hydrogen, C₁₋₆ alkyl, C₆₋₁₀ aryl optionally substituted with one ormore R¹¹, or C₇₋₁₄ aralkyl optionally substituted with one or more R¹¹.In some embodiments, R⁵ is selected from methyl, ethyl, isopropyl, orbutyl. In some embodiments, R⁵ is selected from phenyl or benzyl, eachoptionally substituted with one or more R¹¹.

In some embodiments, R⁶ and R⁷ together with the nitrogen to which theyare attached form a 6-10 membered heterocyclyl optionally substitutedwith one or more R¹⁰. In some embodiments, the heterocyclyl formed by R⁶and R⁷ together with the nitrogen to which they are attached is selectedfrom

each optionally substituted with one or more R¹⁰. In some suchembodiments, the heterocyclyl formed by R⁶ and R⁷ together with thenitrogen to which they are attached can be optionally substituted

In some such embodiments, the heterocyclyl formed by R⁶ and R⁷ togetherwith the nitrogen to which they are attached can be optionallysubstituted

In some such embodiments, the heterocyclyl formed by R⁶ and R⁷ togetherwith the nitrogen to which they are attached can be optionallysubstituted

In some such embodiments, the heterocyclyl formed by R⁶ and R⁷ togetherwith the nitrogen to which they are attached can be optionallysubstituted

In some embodiments, R¹⁰ is C₁₋₆ alkyl. In some embodiments, two geminalR¹⁰ together are oxo. In some other embodiments, the heterocyclyl formedby R⁶ and R⁷ together with the nitrogen to which they are attached isunsubstituted.

In some embodiments, R² is —SR⁵. In some such embodiments, R⁵ is C₆₋₁₀aryl optionally substituted with one or more R¹¹. In some further suchembodiments, R⁵ is optionally substituted phenyl.

In some embodiments, R² is —C(O)R⁸. In some embodiments, R⁸ is selectedfrom —NR¹²R¹³. In some embodiments, each R¹² and R¹³ is independentlyselected from hydrogen, optionally substituted C₁₋₆ alkyl, C₆₋₁₀ aryloptionally substituted with one or more R¹¹, or C₇₋₁₄ aralkyl optionallysubstituted with one or more R¹¹. In some embodiments, each R¹² and R¹³is independently selected from hydrogen, C₁₋₆ alkyl, phenyl optionallysubstituted with one or more R¹¹ or benzyl optionally substituted withone or more R¹¹. In some embodiments, the phenyl or benzyl isunsubstituted.

In some embodiments, R² is —C(O)OR⁵. In some embodiments, R⁵ is hydrogenor C₁₋₆ alkyl.

In any of the embodiments of formula (I) described herein, each R¹¹ isindependently selected from —CN, halogen, optionally substituted C₁₋₆alkyl, optionally substituted C₁₋₆ alkoxy, O—(CH₂)_(n)—C₂₋₈ alkoxy, or—C(O) NR¹²R¹³. In some such embodiments, R¹¹ is selected from —CN, —Cl,—F, —CH₃, —OCH₃, OC₂H₅, —CF₃ or —OCF₃. In some embodiments, R¹¹ is —F.In some embodiments, R¹¹ is —OCF₃. In yet some other embodiments, R¹¹ is—OC₂H₅. In yet some other embodiments, R¹¹ is methyl. In someembodiments, R¹¹ is —O—(CH₂)₂—OCH₃. In some other embodiments, R¹¹ is—C(O)NH₂

Some embodiments disclosed herein with respect to the compounds offormula (I), R³ is selected from the group consisting of—(CH₂)_(n)—(C₆₋₁₀ aryl), —(CH₂)_(n)-(5-10 membered heteroaryl),—(CH₂)_(n)—(C₃₋₁₀ carbocyclyl), and —(CH₂)_(n)-(3-10 memberedheterocyclyl), each optionally substituted with one or more R⁹. In someembodiments, n is 0.

In some embodiments, R³ is —(CH₂)_(n)—(C₆₋₁₀ aryl) optionallysubstituted with one or more R⁹. In some embodiments, R³ is—(CH₂)_(n)-phenyl, optionally substituted with one or more R⁹. In someembodiments, n is 0. In some other embodiments, R³ is unsubstituted—(CH₂)_(n)-phenyl. In some other embodiments, R³ is unsubstitutedphenyl.

In any of the embodiments of formula (I) described herein, R⁹ isselected from halogen, optionally substituted C₁₋₆ alkyl, or —OR⁵. Insome further embodiments, R⁹ is selected from fluoro, chloro. In somefurther embodiments, R⁹ is selected from methyl, ethyl, ortrifluoromethyl. In some embodiments, R⁹ is —OR⁵. In some embodiment, R⁵is selected from hydrogen, C₁₋₆ alkyl or halo substituted C₁₋₆ alkyl. Insome further embodiments, R⁵ is selected from trifluoromethyl or ethyl.In some further embodiments, R⁵ is optionally substituted C₂₋₈alkoxyalkyl. In some embodiment, R⁹ is NR¹⁴R¹⁵. In some suchembodiments, R⁹ is —NH—C(O)R⁸. In some further such embodiments, R⁹ isselected from —NH—C(O)—C₁₋₆ alkyl, or —NH—C(O)—NH₂. In some embodiments,R⁹ is hydroxy.

Some embodiments described herein with respect to compounds of formula(I), R³ is unsubstituted. In some other embodiments, R³ is hydrogen.

In some embodiments, Z is oxygen.

In some embodiments, the bonds represented by a solid and dashed lineare double bonds. In some such embodiments, compounds of formula (I) arealso represented by

In some embodiments, the compound of formula (I) is selected from thegroup consisting of Compounds 85-162, 401-414, 523-545, 550, 551 and 664in Table 1. In some further embodiments, the compound of formula (I) isselected from the group consisting of Compounds 85-162, 401-414,523-538, 540, 541, 543, 545-, 664 and 696-707 of Table 1.

Some alternative embodiments provide compounds of formula (I) with thesame variable definitions as provided above with the exception that R²is selected from 5-10 membered heteroaryl or 3-10 membered heterocyclyl,each optionally substituted with one or more R⁴. One non-limitingexample of these alternative embodiments is where the compound offormula (I) is Compound 708 of Table 1.

Formula II

Some embodiments disclosed herein relate to a compound of formula (II)as described above or a pharmaceutically acceptable salt thereof.

Some embodiments disclosed herein with respect to the compounds offormula (II), formula (II) is also represented by formula (IIa):

R³ is selected from the group consisting of —(CH₂)_(n)—(C₆₋₁₀ aryl),—(CH₂)_(n)-(5-10 membered heteroaryl), —(CH₂)_(n)—(C₃₋₁₀ carbocyclyl),and —(CH₂)_(n)-(3-10 membered heterocyclyl), each optionally substitutedwith one or more R⁹; and

each R⁹ is independently selected from the group consisting of halogen,optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl,optionally substituted C₂₋₆ alkynyl, optionally substituted C₁₋₆alkylthio, optionally substituted C₂₋₈ alkoxyalkyl, optionallysubstituted C₃₋₁₀ carbocyclyl, optionally substituted C₆₋₁₀ aryl, —OR⁵,—NR¹⁴R¹⁵, —C(O)R⁸, —SO₂R¹⁶, and —NO₂.

In some embodiments, R² is selected from optionally substituted C₁₋₆alkyl. In some embodiments, R² is selected from methyl, ethyl,isopropyl, or trifluoromethyl. In some embodiments, R² is methyl.

Some embodiments disclosed herein with respect to the compounds offormula (II), R³ is hydrogen. In some such embodiments, the compound offormula (II) is selected from the group consisting of compounds 562-565,567, 662 and 663 of Table 1.

Some embodiments disclosed herein with respect to the compounds offormula (II), R³ is selected from the group consisting of—(CH₂)_(n)—(C₆₋₁₀ aryl), —(CH₂)_(n)-(5-10 membered heteroaryl),—(CH₂)_(n)—(C₃₋₁₀ carbocyclyl), and —(CH₂)_(n)-(3-10 memberedheterocyclyl), each optionally substituted with one or more R⁹. In someembodiments, n is 0.

In some embodiments, R³ is selected from —(CH₂)_(n)—(C₆₋₁₀ aryl),optionally substituted with one or more R⁹. In some embodiments, R³ is—(CH₂)_(n)-phenyl optionally substituted with one or more R⁹. In someembodiments, R³ is phenyl, optionally substituted with one or more R⁹.In some embodiments, R³ is unsubstituted phenyl. In some embodiments, R³is unsubstituted —(CH₂)_(n)—(C₆₋₁₀ aryl).

In some embodiments, R³ is selected from —(CH₂)_(n)-(9 memberedheterocyclyl), optionally substituted with one or more R⁹. In someembodiments, R³ is selected from

each optionally substituted with one or more R⁹. In some suchembodiments, R³ is optionally substituted

In some such embodiments, R³ is optionally substituted

In some such embodiments, R³ is optionally substituted

In some such embodiments, R³ is optionally substituted

In some embodiments, R³ is unsubstituted.

In some embodiments, R³ is selected from —(CH₂)_(n)-(10 memberedheterocyclyl), optionally substituted with one or more R⁹. In someembodiments, n is 0. In some embodiments, R³ is selected from

each optionally substituted with one or more R⁹. In some embodiments, R³is unsubstituted.

In any of embodiments of formula (II) described herein, each R⁹ isindependently selected from halogen, optionally substituted C₁₋₆ alkyl,—OR⁵, —NR¹⁴R¹⁵ or —C(O)R⁸. In some embodiments, R⁹ is selected frommethyl, ethyl, propyl isopropyl, or trifluoromethyl. In someembodiments, R⁹ is selected from fluoro or chloro.

In some embodiments, R⁹ is —OR⁵, and wherein R⁵ is selected fromoptionally substituted C₁₋₆ alkyl. In some embodiments, R⁵ isunsubstituted C₁₋₆ alkyl. In some embodiments, R⁵ is selected frommethyl, ethyl, propyl, isopropyl or trifluoromethyl. In someembodiments, R⁵ is methyl. In some other embodiments, R⁵ istrifluoromethyl.

In some embodiments, R⁹ is —NR¹⁴R¹⁵, and wherein each R¹⁴ and R¹⁵ isindependently selected from hydrogen, C₁₋₆ alkyl or —C(O)R⁸. In someembodiments, R⁸ is selected from optionally substituted C₁₋₆ alkyl, —OR⁵or —NR¹²R¹³. In some embodiments, each R¹² and R¹³ is independentlyselected from hydrogen or C₁₋₆ alkyl. In some embodiments, each R¹² andR¹³ is independently selected from hydrogen or methyl. In someembodiments, R⁵ is selected from hydrogen or C₁₋₆ alkyl. In someembodiments, each R¹⁴ and R¹⁵ is independently selected from hydrogen,methyl, ethyl, —C(O)NH₂, —C(O)NHCH₃, —C(O)N(CH₃)₂, —C(O)OH or —C(O)OEt.

In some embodiments, R⁹ is —C(O)R⁸. In some embodiments, R⁸ is selectedfrom optionally substituted C₁₋₆ alkyl or —NR¹²R¹³. In some embodiments,R⁸ is selected from methyl, —NH₂ or —NHCH₃.

In some embodiments, all Y is CR⁴.

In some embodiments, at least one Y in

is N. In some embodiments,

is selected from

each optionally substituted with one to four R⁴. In some suchembodiments,

is optionally substituted

In some such embodiments,

is optionally substituted

In some such embodiments,

is optionally substituted

In some embodiments, at least one Y in

is N. In some embodiments,

is selected from

each optionally substituted with one to four R⁴. In some suchembodiments,

is optionally substituted

In some such embodiments,

is optionally substituted

In some such embodiments,

is optionally substituted

In some other embodiments, two of Y in

are N. In some embodiments,

is selected from

each optionally substituted with one to three R⁴. In some suchembodiments,

is optionally substituted

In some such embodiments,

is optionally substituted

In some such embodiments,

is optionally substituted

In some such embodiments,

is optionally substituted

In some such embodiments,

is optionally substituted

In some such embodiments,

is optionally substituted

In some such embodiments,

is optionally substituted

In some such embodiments,

is optionally substituted

In some other embodiments, two of Y in

are N. In some such embodiments,

is selected from

each optionally substituted with one to three R⁴. In some such furtherembodiments,

is selected from

each optionally substituted with one to three R⁴. In some suchembodiments,

is optionally substituted

In some such embodiments,

is optionally substituted

In some such embodiments,

is optionally substituted

In some such embodiments,

is optionally substituted

In some such embodiments,

is optionally substituted

In some such embodiments,

is optionally substituted

In some such embodiments,

is optionally substituted

In some such embodiments,

is optionally substituted

In any of the embodiments of

of formula (II) or (IIa) described herein, R⁴ is selected from hydrogen,halogen, —CN, optionally substituted C₁₋₆ alkyl, optionally substitutedC₁₋₆ alkoxy or 5 membered heteroaryl optionally substituted with one ormore R¹¹. In some embodiments, R⁴ is selected from hydrogen, fluoro,chloro, methyl, ethyl, methoxy, ethoxy or thiazolyl.

In some other embodiments, two adjacent R⁴ together with the carbonatoms to which they are attached form a fused ring selected fromoptionally substituted 5 or 6 membered heteroaryl or optionallysubstituted 5 or 6 membered heterocyclyl.

In some embodiments, the optionally substituted 5 or 6 memberedheterocyclyl formed by two adjacent R⁴ together with the carbon atoms towhich they are attached is selected from

wherein each R¹⁷ is independently selected from hydrogen, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₃₋₆ cycloalkyl, C₆₋₁₀aryl optionally substituted with one or more R¹¹, C₇₋₁₄ aralkyloptionally substituted with one or more R¹¹, or optionally substitutedC₂₋₈ alkoxyalkyl. In some such embodiments, R¹⁷ is selected fromhydrogen, methyl, ethyl, —(CH₂)₂OH or —(CH₂)₂OCH₃. In some further suchembodiments, the optionally substituted 5 or 6 membered heterocyclyl isselected from

In some further such embodiments, the optionally substituted 5 or 6membered heterocyclyl is selected from

In some embodiments, the optionally substituted 5 or 6 memberedheterocyclyl is substituted with one or more substituents selected fromC₁₋₆ alkyl or halogen. In some other embodiments, the 5 or 6 memberedheterocyclyl is unsubstituted.

In some embodiments, the optionally substituted 5 or 6 memberedheteroaryl formed by two adjacent R⁴ together with the carbon atoms towhich they are attached is selected from

wherein each R¹⁸ is independently selected from hydrogen, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₃₋₆ cycloalkyl, C₆₋₁₀aryl optionally substituted with one or more R¹¹, C₇₋₁₄ aralkyloptionally substituted with one or more R¹¹, or optionally substitutedC₂₋₈ alkoxyalkyl. In some such embodiments, R¹⁸ is selected fromhydrogen or methyl. In some further such embodiments, the optionallysubstituted 5 or 6 membered heteroaryl is selected from

In some embodiments, the optionally substituted 5 or 6 memberedheterocyclyl is substituted with one or more substituents selected fromC₁₋₆ alkyl or halogen. In some other embodiments, the 5 or 6 memberedheterocyclyl is unsubstituted.

In some embodiments, the substituent on the 5 or 6 membered heteroarylor 5 or 6 membered heterocyclyl formed by two adjacent R⁴ together withthe carbon atoms to which they are attached is selected from C₁₋₆ alkyl,C₁₋₆ alkoxy, oxo or halogen. In some further embodiments, thesubstituent is selected from methyl, fluoro, or oxo. In someembodiments, the substituent is oxo. In some such embodiments, the 5 or6 membered heteroaryl or 5 or 6 membered heterocyclyl are selected from

In some embodiments of

R¹⁷ is alkyl.

In some embodiments, Z is oxygen.

In some embodiments, the bonds represented by a solid and dashed lineare double bonds, provided that when the optionally substituted 5 or 6membered heteroaryl formed by two adjacent R⁴ together with the carbonatoms to which they are attached is selected from

one of the bonds represented by a solid and dashed line in

is a single bond. In some embodiments, the bonds represented by a solidand dashed line are double bonds in formula (IIa). In some suchembodiments, compounds of formula (II) are also represented by

In some such embodiments, compounds of formula (IIa) are alsorepresented by

In some embodiments, the compound of formula (II) is selected from thegroup consisting of Compounds 163-216, 241-243, 245, 246, 248-252, 254,255, 258-261, 263, 415-430, 432, 552-567, 629, 662 and 663 of Table 1.In some further embodiments, the compound of formula (II) is selectedfrom the group consisting of Compounds 163-216, 241-243, 245, 246,248-252, 254, 255, 258-261, 263, 415-430, 432, 552-561, 566 and 629 ofTable 1.

Formula III

Some embodiments disclosed herein relate to a compound of formula (III)as described above or a pharmaceutically acceptable salt thereof.

Some embodiments disclosed herein with respect to the compounds offormula (III), R³ is selected from the group consisting of—(CH₂)_(n)—(C₆₋₁₀ aryl), —(CH₂)_(n)-(5-10 membered heteroaryl),—(CH₂)_(n)—(C₃₋₁₀ carbocyclyl), and —(CH₂)_(n)-(3-10 memberedheterocyclyl), each optionally substituted with one or more R⁹; and eachR⁹ is independently selected from the group consisting of halogen,optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl,optionally substituted C₂₋₆ alkynyl, optionally substituted C₁₋₆alkylthio, optionally substituted C₂₋₈ alkoxyalkyl, optionallysubstituted C₃₋₁₀ carbocyclyl, optionally substituted C₆₋₁₀ aryl, —OR⁵,—NR¹⁴R¹⁵, —(O)R⁸, —SO₂R¹⁶, and —NO₂.

In some embodiments, R¹ is selected from halogen, C₁₋₆ alkyl optionallysubstituted with one or more R⁴, C₆₋₁₀ aryl optionally substituted withone or more R⁴, or 5 to 6-membered heteroaryl optionally substitutedwith one or more R⁴. In some embodiments, R¹ is bromo or fluoro. In someembodiments, R¹ is methyl optionally substituted with one or more R⁴. Insome embodiments, R¹ is methyl. In some embodiments, R¹ is phenyloptionally substituted with one or more R⁴. In some embodiments, R¹ ispyridazinyl optionally substituted with one or more R⁴ In someembodiments, R¹ is unsubstituted phenyl. In some embodiments, R¹ ispyrazolyl or 1-methyl pyrazolyl optionally substituted with one or moreR⁴. In some embodiment, R⁴ is selected from halogen.

Some embodiments disclosed herein with respect to the compounds offormula (III), R³ is selected from the group consisting of—(CH₂)_(n)—(C₆₋₁₀ aryl), —(CH₂)_(n)-(5-10 membered heteroaryl),—(CH₂)_(n)—(C₃₋₁₀ carbocyclyl), and —(CH₂)_(n)-(3-10 memberedheterocyclyl), each optionally substituted with one or more R⁹. In someembodiments, n is 0.

In some embodiments, R³ is selected from —(CH₂)_(n)—(C₆₋₁₀ aryl)optionally substituted with one or more R⁹.

In some embodiments, R³ is phenyl, optionally substituted with one ormore R⁹. In some other embodiments, R³ is unsubstituted phenyl.

Some embodiments disclosed herein with respect to the compounds offormula (III), R³ is hydrogen. In some such embodiments, the compound offormula (III) is selected from the group consisting of compounds 576,578, 590, 595, 611-613, 616, 618, 621-623, 637 and 638 of Table 1.

In any of embodiments of formula (III) described herein, R⁹ is selectedfrom cyano, halogen, optionally substituted C₁₋₆ alkyl, or optionallysubstituted C₁₋₆ alkoxy. In some further embodiments, R⁹ is selectedfrom cyano, fluoro, chloro, methyl, ethyl, ethoxy, methoxy,trifluoromethyl or trifluoromethoxy. In some embodiments, R⁹ is ethoxy.In some embodiments, R⁹ is trifluoromethoxy. In still some otherembodiment, R⁹ is difluoromethoxy.

In any of the embodiments of formula (III) described herein, ring A isselected from 6-membered heteroaryl, 5-membered heterocyclyl or6-membered heterocyclyl, each optionally substituted with one or moreR⁴.

In some such embodiments, ring A is selected from

each optionally substituted with one or more R⁴; and wherein each R¹⁷ isindependently selected from hydrogen, optionally substituted C₁₋₆ alkyl,optionally substituted C₃₋₆ cycloalkyl, optionally substituted C₂₋₈alkoxyalkyl, optionally substituted C-carboxy, acyl, C₆₋₁₀ aryloptionally substituted with one or more R¹¹, or C₇₋₁₄ aralkyl optionallysubstituted with one or more R¹¹.

In some embodiments, ring A is selected from

each optionally substituted with one or more R⁴.

In some embodiments, ring A is selected from

each optionally substituted with one or more R⁴.

In some embodiments, ring A is optionally substituted

In some embodiments, ring A is optionally substituted

In some embodiments, ring A is optionally substituted

In some embodiments, ring A is optionally substituted

In some embodiments, ring A is optionally substituted

In some embodiments, ring A is optionally substituted

In some embodiments, ring A is optionally substituted

In some embodiments, ring A is optionally substituted

In some embodiments, ring A is optionally substituted

In some embodiments, ring A is optionally substituted

In some embodiments, ring A is optionally substituted

In some embodiments, ring A is optionally substituted

In some embodiments, ring A is optionally substituted

In some embodiments, ring A is optionally substituted

In some embodiments, ring A is optionally substituted

In some embodiments, ring A is optionally substituted

In some embodiments, ring A is optionally substituted

In any of embodiments of ring A as described herein in formula (III),R¹⁷ is selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl,—(CH₂)₂F, —(CH₂)₂OH, —(CH₂)₂OCH₃, —(CH₂)₂OC₂H₅, —(CH₂)₂OC₃H₇,—C(O)O^(t)Bu, —C(O)CH₃ or benzyl.

In some further such embodiments, ring A is selected from

each optionally substituted with one or more R⁴.

In some such further embodiments, ring A is selected from

each optionally substituted with one or more R⁴.

In any of the embodiments of formula (III) described herein, R⁴ isselected from halogen, optionally substituted C₁₋₆ alkyl, or C₇₋₁₄aralkyl optionally substituted with one or more R¹¹, or two geminal R⁴together are oxo. In some further embodiments, R⁴ is selected fromfluoro, methyl, trifluoromethyl, or benzyl. In some embodiments, twogeminal R⁴ together are oxo.

In some embodiments, ring A is unsubstituted.

In some embodiments, Z is oxygen.

In some embodiments, the bonds represented by a solid and dashed lineare double bonds, provided that when ring A is

one of the bonds represented by a solid and dashed line is a singlebond. In some such embodiments, compounds of formula (III) are alsorepresented by

In some embodiments, the compound of formula (III) is selected from thegroup consisting of Compounds 29-63, 392-400, 568-628, 630-661, and 665of Table 1. In some further embodiments, the compound of formula (III)is selected from the group consisting of Compounds 29-63, 392-400,568-574, 577, 579-584, 586-589, 591-594, 596-608, 614, 615, 617, 619,620, 624-626, 631, 634-636, 640, 642-655, 657-661, 665, and 669-695 ofTable 1.

Formula IV

Some embodiments disclosed herein relate to a compound of formula (IV)as described above or a pharmaceutically acceptable salt thereof.

In some embodiments, R¹ is selected from the group consisting ofhydrogen, C₁₋₆ alkyl optionally substituted with one or more R⁴, or5-membered heteroaryl optionally substituted with one or more R⁴.

In some embodiments, R¹ is selected from methyl, phenyl, pyrazolyl, or1-methyl pyrazolyl, each optionally substituted with one or more R⁴. Insome embodiments, R¹ is methyl. In some embodiments, R¹ is unsubstitutedphenyl. In some embodiments, R¹ is unsubstituted pyrazolyl. In yet someother embodiments, R¹ is unsubstituted 1-methyl pyrazolyl.

In some embodiments, R² is selected from hydrogen or optionallysubstituted C₁₋₆ alkyl.

In some embodiments, all Y are CR⁴. In some other embodiment, at leastone Y is nitrogen.

In some embodiments, R⁴ is selected from halogen, C₁₋₆ alkyl or C₁₋₆alkoxy. In some embodiments, R⁴ is selected from fluoro or methyl.

In some embodiments, m is 1. In some embodiments, m is 2. In someembodiments, m is 3.

In some embodiments, Z is oxygen.

In some embodiments, the bonds represented by a solid and dashed lineare double bonds.

In some embodiments, the compound of formula (IV) is selected from thegroup consisting of Compounds 21-26 of Table 1.

Formula V

Some embodiments disclosed herein relate to a compound of formula (V) asdescribed above or a pharmaceutically acceptable salt thereof.

In some embodiments, each R² is independently selected from hydrogen,C₁₋₆ alkyl or —OR⁵.

In some embodiments, each R² is hydrogen.

In some embodiments, R³ is —(CH₂)_(n)—(C₆₋₁₀ aryl), optionallysubstituted with one or more R⁹. In some embodiments, R³ is phenyl,optionally substituted with one or more R⁹. In some other embodiments,R³ is unsubstituted phenyl.

In some embodiments, R⁹ is selected from halogen, optionally substitutedC₁₋₆ alkyl, optionally substituted C₂₋₈ alkoxyalkyl, —OR⁵, or —NR¹⁴R¹⁵.In some embodiments, R⁹ is selected from fluoro, chloro, methyl, ethyl,methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, —NHCH₃, —NH₂, or—NHC(O)CH₃. In some embodiments, R⁹ is trifluoromethoxy.

In some embodiments, ring A is a C₅ carbocyclyl optionally substitutedwith one or more R⁴. In some embodiments, ring A is a C₆ carbocyclyloptionally substituted with one or more R⁴. In some other embodiments,ring A is unsubstituted.

In some embodiments, wherein R⁴ is selected from halogen, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₁₋₆ alkoxy, orindependently two geminal R⁴ together are oxo.

In some embodiments, ring A is an unsubstituted C₅₋₇ carbocyclyl.

In some embodiments, Z is oxygen.

In some embodiments, the bonds represented by a solid and dashed lineare double bonds.

In some embodiments, the compound of formula (V) is selected from thegroup consisting of Compounds 27 and 28 of Table 1.

Formula VIa

Some embodiments disclosed herein relate to a compound of formula (VIa)as described above or a pharmaceutically acceptable salt thereof.

In some embodiments, R is a C₄ carbocyclyl optionally substituted withone or more R⁴.

In some embodiments, R¹ is a C₅ carbocyclyl optionally substituted withone or more R⁴.

In some embodiments, R¹ is a C₆ carbocyclyl optionally substituted withone or more R⁴.

In some embodiments, R⁴ is selected from halogen, optionally substitutedC₁₋₆ alkyl, or optionally substituted C₁₋₆ alkoxy. In some embodiments,R⁴ is selected from fluoro, chloro, methyl, methoxy, ethoxy,trifluoromethyl, or trifluoromethoxy.

In some other embodiments, R¹ is unsubstituted.

In some embodiments, each R² is independently selected from hydrogen,halogen, optionally substituted C₁₋₆ alkyl, —OR⁵ or —NR⁶R⁷. In someembodiments, R² is hydrogen. In some embodiment, R² is halogen.

In some embodiments, R² is optionally substituted C₁₋₆ alkyl. In someembodiments, R² is methyl. In some other embodiments, R² istrifluoromethyl.

In some embodiments, R³ is selected from —(CH₂)_(n)—(C₆₋₁₀ aryl),optionally substituted with one or more R⁹. In some embodiments, R³ isphenyl, optionally substituted with one or more R⁹.

In some embodiments, R⁹ is selected from halogen, optionally substitutedC₁₋₆ alkyl, optionally substituted C₂₋₈ alkoxyalkyl, —OR⁵, or —NR¹⁴R¹⁵.In some embodiments, R⁹ is selected from fluoro, chloro, methyl, ethyl,methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, —NHCH₃, —NH₂, or—NHC(O)CH₃.

In some embodiment, R³ is unsubstituted phenyl.

In some embodiments, Z is oxygen.

In some embodiments, the bonds represented by a solid and dashed lineare double bonds.

In some embodiments, the compound of formula (VIa) is selected from thegroup consisting of Compounds 64-66 of Table 1.

Formula VII

Some embodiments disclosed herein relate to a compound of formula (VII)as described above or a pharmaceutically acceptable salt thereof.

In some embodiments, each R² is independently selected from hydrogen,halogen, optionally substituted C₁₋₆ alkyl, —OR⁵ or —NR⁶R⁷. In someembodiments, R² is hydrogen. In some embodiments, R² is halogen. In someembodiments, R² is optionally substituted C₁₋₆ alkyl. In some furtherembodiments, R² is methyl or trifluoromethyl.

In some embodiments, R³ is selected from —(CH₂)_(n)—(C₆₋₁₀ aryl),optionally substituted with one or more R⁹. In some embodiments, R³ isphenyl optionally substituted with one or more R⁹.

In some embodiments, R⁹ is selected from halogen, optionally substitutedC₁₋₆ alkyl, optionally substituted C₂₋₈ alkoxyalkyl, —OR⁵, or —NR¹⁴R¹⁵.In some embodiments, R⁹ is selected from fluoro, chloro, methyl, ethyl,methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, —NHCH₃, —NH₂, or—NHC(O)CH₃.

In some embodiments, R³ is unsubstituted phenyl.

In some embodiments, Q is C(O). In some other embodiments, Q isS(O)_(t). In some embodiments, t is 2.

In some embodiments, R¹⁶ is selected from optionally substituted C₁₋₆alkyl, C₆₋₁₀ aryl optionally substituted with one or more R¹¹, C₇₋₁₄aralkyl optionally substituted with one or more R¹¹, —NR¹²R¹³, or —OR⁵.In some embodiments, R¹⁶ is optionally substituted C₁₋₆ alkyl. In someembodiments, R¹⁶ is selected from methyl, ethyl, propyl, isopropyl, orbutyl. In some embodiments, R¹⁶ is phenyl optionally substituted withone or more R¹¹. In some other embodiments, R¹⁶ is unsubstituted phenyl.In some embodiments, R¹⁶ is benzyl optionally substituted with one ormore R¹¹. In some other embodiments, R¹⁶ is unsubstituted benzyl. Insome embodiments, R¹⁶ is —NR¹²R¹³. In some embodiments, each R¹² and R¹³is independently selected from hydrogen or optionally substituted C₁₋₆alkyl. In some embodiments, R¹⁶ is —OR⁵. In some embodiments, R⁵ isselected from hydrogen or optionally substituted C₁₋₆ alkyl. In somefurther embodiments, R⁵ is selected from methyl, ethyl, propyl,isopropyl, or butyl.

In some embodiments, Z is oxygen.

In some embodiments, the bonds represented by a solid and dashed lineare double bonds.

In some embodiments, the compound of formula (VII) is selected from thegroup consisting of Compounds 67-76 of Table 1.

Formula VIb

Some embodiments disclosed herein relate to a compound of formula (VIb)as described above or a pharmaceutically acceptable salt thereof.

In some embodiments, R¹ is selected from C₁₋₆ alkyl optionallysubstituted with one or more R⁴, C₆₋₁₀ aryl optionally substituted withone or more R⁴, or 5-10 membered heteroaryl optionally substituted withone or more R⁴. In some embodiments, R¹ is selected from C₁₋₆ alkyloptionally substituted with one or more R⁴. In some further embodiments,R¹ is selected from methyl, ethyl, propyl, or isopropyl. In some furtherembodiments, R¹ is phenyl optionally substituted with one or more R⁴. Insome embodiments, R¹ is selected from 5 or 6 membered heteroaryl, eachoptionally substituted with one or more R⁴. In some further embodiments,R¹ is selected from pyrazolyl or 1-methyl pyrazolyl, each optionallysubstituted with one or more R⁴. In some other embodiment, R¹ isunsubstituted.

In some embodiments, R⁴ is selected from halogen or optionallysubstituted C₁₋₆ alkyl. In some embodiments, R⁴ is fluoro.

In some embodiments, each R² is independently selected from hydrogen,halogen, or optionally substituted C₁₋₆ alkyl. In some embodiments, R²is hydrogen.

In some embodiments, R³ is —(CH₂)₁₋₄—(C₆₋₁₀ aryl), optionallysubstituted with one or more R⁹. In some embodiments, R³ is—(CH₂)₁₋₄-phenyl, optionally substituted with one or more R⁹. In someother embodiments, R³ is unsubstituted. In some embodiments, R³ is—(CH₂)-phenyl, optionally substituted with one or more R⁹. In someembodiments, R³ is —(CH₂)₂-phenyl, optionally substituted with one ormore R⁹. In some other embodiments, R³ is unsubstituted.

In some embodiments, R⁹ is selected from halogen, optionally substitutedC₁₋₆ alkyl, optionally substituted C₂₋₈ alkoxyalkyl, —OR⁵, —C(O)R⁸ or—NR¹⁴R¹⁵. In some further embodiments, R⁹ is selected from fluoro,chloro, methyl, ethyl, methoxy, ethoxy, trifluoromethyl,trifluoromethoxy, —C(O)CH₃, —NHCH₃, —NH₂, or —NHC(O)CH₃.

In some embodiments, Z is oxygen.

In some embodiments, the bonds represented by a solid and dashed lineare double bonds.

In some embodiments, the compound of formula (VIb) is selected from thegroup consisting of Compounds 77-80 of Table 1.

Formula VIII

Some embodiments disclosed herein relate to a compound of formula (VIII)as described above or a pharmaceutically acceptable salt thereof.

In some embodiments, R³ is selected from optionally substituted C₁₋₆alkyl or —(CH₂)_(n)—(C₆₋₁₀ aryl) optionally substituted with one or moreR⁹. In some embodiments, R³ is —(CH₂)_(n)—(C₆₋₁₀ aryl) optionallysubstituted with one or more R⁹. In some embodiments, R³ is phenyloptionally substituted with one or more R⁹.

In some embodiments, R⁹ is selected from halogen, optionally substitutedC₁₋₆ alkyl, optionally substituted C₂₋₈ alkoxyalkyl, —OR⁵, —C(O)R⁸ or—NR¹⁴R¹⁵. In some further embodiments, R⁹ is selected from fluoro,chloro, methyl, ethyl, methoxy, ethoxy, trifluoromethyl,trifluoromethoxy, —C(O)CH₃, —NHCH₃, —NH₂, or —NHC(O)CH₃. In someembodiments, R⁹ is trifluoromethoxy.

In some other embodiments, R³ is unsubstituted phenyl.

In some embodiments, R³ is optionally substituted C₁₋₆ alkyl. In somefurther embodiments, R³ is C₁₋₆ alkyl.

In some embodiments, each R¹⁷ is independently selected from hydrogen,halogen, optionally substituted C₁₋₆ alkyl or oxo. In some embodiments,each R¹⁷ is hydrogen.

In some embodiments, two adjacent R¹⁷ together with the carbon atoms towhich they are attached form a fused phenyl optionally substituted withone or more R⁴. In some further embodiments, at least one R¹⁷ is oxo. Insome embodiments, at least one R¹⁷ is optionally substituted C₁₋₆ alkyl.In some embodiments, the fused phenyl is unsubstituted.

In some embodiments, two adjacent R¹⁷ together with the carbon atoms towhich they are attached form a fused 5-6 membered heteroaryl, optionallysubstituted with one or more R⁴. In some embodiments, at least one R¹⁷is oxo. In some embodiments, at least one R¹⁷ is optionally substitutedC₁₋₆ alkyl. In some embodiments, the fused 5-6 membered heteroaryl isunsubstituted.

In some embodiments, R⁴ is selected from halogen or optionallysubstituted C₁₋₆ alkyl.

In some embodiments, n is 0. In some other embodiments, n is 1. In yetsome other embodiments, n is 3.

In some embodiments, Z is oxygen.

In some embodiments, the compound of formula (VIII) is selected from thegroup consisting of Compounds 81, 82, and 513-519 of Table 1.

Formula IX

Some embodiments disclosed herein relate to a compound of formula (IX)as described above or a pharmaceutically acceptable salt thereof.

In some embodiments, R¹ is selected from C₁₋₆ alkyl optionallysubstituted with one or more R⁴, C₆₋₁₀ aryl optionally substituted withone or more R⁴, or 5-10 membered heteroaryl optionally substituted withone or more R⁴. In some embodiments, R¹ is C₁₋₆ alkyl optionallysubstituted with one or more R⁴. In some embodiments, R¹ is C₆₋₁₀ aryloptionally substituted with one or more R⁴.

In some further embodiments, R¹ is phenyl optionally substituted withone or more R⁴. In some embodiments, R¹ is 5 or 6 membered heteroaryloptionally substituted with one or more R⁴. In some further embodiments,R¹ is pyrazolyl or 1-methyl pyrazolyl optionally substituted with one ormore R⁴.

In some embodiments, R⁴ is selected from halogen, optionally substitutedC₁₋₆ alkyl, or optionally substituted C₁₋₆ alkoxy.

In some embodiments, R¹ is unsubstituted.

In some embodiments, each R² is independently selected from hydrogen,halogen or optionally substituted C₁₋₆ alkyl. In some embodiments, R² ishydrogen.

In some embodiments, R³ is —(CH₂)_(n)—(C₆₋₁₀ aryl), optionallysubstituted with one or more R⁹. In some further embodiments, R³ isphenyl optionally substituted with one or more R⁹. In some otherembodiments, R³ is unsubstituted.

In some embodiments, R⁹ is selected from halogen, optionally substitutedC₁₋₆ alkyl, optionally substituted C₂₋₈ alkoxyalkyl, —OR⁵, —C(O)R⁸ or—NR¹⁴R¹⁵. In some further embodiments, R⁹ is selected from fluoro,chloro, methyl, ethyl, methoxy, ethoxy, trifluoromethyl,trifluoromethoxy, —C(O)CH₃, —NHCH₃, —NH₂, or —NHC(O)CH₃.

In some embodiments, Z is oxygen.

In some embodiments, the compound of formula (IX) is selected from thegroup consisting of Compounds 83, 84, 520-522 of Table 1.

Some embodiments described herein relate to one or more compoundsselected from the group consisting of Compounds 1-20, 217-240, 244, 247,253, 256, 257, 262, 264-283, 285, 287-339, 341-391, 431, 433, 434,438-440, 442, 446-512, 546-549, 575, 585, 609, 610, 627, 628, 630, 632,633, 639, 641, 656, 666-668, 708 and 709 of Table 1.

In some embodiments, compounds are selected from the following compoundsas listed in Table 1.

TABLE 1 Compd. # Structure 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

172

173

174

175

176

177

178

179

180

181

182

183

184

185

186

187

188

189

190

191

192

193

194

195

196

197

198

199

200

201

202

203

204

205

206

207

208

209

210

211

212

213

214

215

216

217

218

219

220

221

222

223

224

225

226

227

228

229

230

231

232

233

234

235

236

237

238

239

240

241

242

243

244

245

246

247

248

249

250

251

252

253

254

255

256

257

258

259

260

261

262

263

264

265

266

267

268

269

270

271

272

273

274

275

276

277

278

279

280

281

282

283

285

287

288

289

290

291

292

293

294

295

296

297

298

299

300

301

302

303

304

305

306

307

308

309

310

311

312

313

314

315

316

317

318

319

320

321

322

323

324

325

326

327

328

329

330

331

332

333

334

335

336

337

338

339

341

342

343

344

345

346

347

348

349

350

351

352

353

354

355

356

357

358

359

360

361

362

363

364

365

366

367

368

369

370

371

372

373

374

375

376

377

378

379

380

381

382

383

384

385

386

387

388

389

390

391

392

393

394

395

396

397

398

399

400

401

402

403

404

405

406

407

408

409

410

411

412

413

414

415

416

417

418

419

420

421

422

423

424

425

426

427

428

429

430

431

432

433

434

438

439

440

442

446

447

448

449

450

451

452

453

454

455

456

457

458

459

460

461

462

463

464

465

466

467

468

469

470

471

472

473

474

475

476

477

478

479

480

481

482

483

484

485

486

487

488

489

490

491

492

493

494

495

496

497

498

499

500

501

502

503

504

505

506

507

508

509

510

511

512

513

514

515

516

517

518

519

520

521

522

523

524

525

526

527

528

529

530

531

532

533

534

535

536

537

538

539

540

541

542

543

544

545

546

547

548

549

550

551

552

553

554

555

556

557

558

559

560

561

562

563

564

565

566

567

568

569

570

571

572

573

574

575

576

577

578

579

580

581

582

583

584

585

586

587

588

589

590

591

592

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595

596

597

598

599

600

601

602

603

604

605

606

607

608

609

610

611

612

613

614

615

616

617

618

619

620

621

622

623

624

625

626

627

628

629

630

631

632

633

634

635

636

637

638

639

640

641

642

643

644

645

646

647

648

649

650

651

652

653

654

655

656

657

658

659

660

661

662

663

664

665

666

667

668

669

670

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675

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677

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679

680

681

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684

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709

Administration and Pharmaceutical Compositions

Some embodiments include pharmaceutical compositions comprising: (a) asafe and therapeutically effective amount of a compound described herein(including enantiomers, diastereoisomers, tautomers, polymorphs, andsolvates thereof), or pharmaceutically acceptable salts thereof; and (b)a pharmaceutically acceptable carrier, diluent, excipient or combinationthereof.

The compounds are administered at a therapeutically effective dosage,e.g., a dosage sufficient to provide treatment for the disease statespreviously described. While human dosage levels have yet to be optimizedfor the compounds of the preferred embodiments, generally, a daily dosefor most of the compounds described herein is from about 0.25 mg/kg toabout 120 mg/kg or more of body weight, from about 0.5 mg/kg or less toabout 70 mg/kg, from about 1.0 mg/kg to about 50 mg/kg of body weight,or from about 1.5 mg/kg to about 10 mg/kg of body weight. Thus, foradministration to a 70 kg person, the dosage range would be from about17 mg per day to about 8000 mg per day, from about 35 mg per day or lessto about 7000 mg per day or more, from about 70 mg per day to about 6000mg per day, from about 100 mg per day to about 5000 mg per day, or fromabout 200 mg to about 3000 mg per day. The amount of active compoundadministered will, of course, be dependent on the subject and diseasestate being treated, the severity of the affliction, the manner andschedule of administration and the judgment of the prescribingphysician.

Administration of the compounds disclosed herein or the pharmaceuticallyacceptable salts thereof can be via any of the accepted modes ofadministration for agents that serve similar utilities including, butnot limited to, orally, subcutaneously, intravenously, intranasally,topically, transdermally, intraperitoneally, intramuscularly,intrapulmonarilly, vaginally, rectally, or intraocularly. Oral andparenteral administrations are customary in treating the indicationsthat are the subject of the preferred embodiments.

The compounds useful as described above can be formulated intopharmaceutical compositions for use in treatment of these conditions.Standard pharmaceutical formulation techniques are used, such as thosedisclosed in Remington's The Science and Practice of Pharmacy, 21st Ed.,Lippincott Williams & Wilkins (2005), incorporated by reference in itsentirety.

In addition to the selected compound useful as described above, comeembodiments include compositions containing apharmaceutically-acceptable carrier. The term“pharmaceutically-acceptable carrier”, as used herein, means one or morecompatible solid or liquid filler diluents or encapsulating substances,which are suitable for administration to a mammal. The term“compatible”, as used herein, means that the components of thecomposition are capable of being commingled with the subject compound,and with each other, in a manner such that there is no interaction,which would substantially reduce the pharmaceutical efficacy of thecomposition under ordinary use situations. Pharmaceutically-acceptablecarriers must, of course, be of sufficiently high purity andsufficiently low toxicity to render them suitable for administrationpreferably to an animal, preferably mammal being treated.

Some examples of substances, which can serve aspharmaceutically-acceptable carriers or components thereof, are sugars,such as lactose, glucose and sucrose; starches, such as corn starch andpotato starch; cellulose and its derivatives, such as sodiumcarboxymethyl cellulose, ethyl cellulose, and methyl cellulose; powderedtragacanth; malt; gelatin; talc; solid lubricants, such as stearic acidand magnesium stearate; calcium sulfate; vegetable oils, such as peanutoil, cottonseed oil, sesame oil, olive oil, corn oil and oil oftheobroma; polyols such as propylene glycol, glycerine, sorbitol,mannitol, and polyethylene glycol; alginic acid; emulsifiers, such asthe TWEENS; wetting agents, such sodium lauryl sulfate; coloring agents;flavoring agents; tableting agents, stabilizers; antioxidants;preservatives; pyrogen-free water; isotonic saline; and phosphate buffersolutions.

The choice of a pharmaceutically-acceptable carrier to be used inconjunction with the subject compound is basically determined by the waythe compound is to be administered.

The compositions described herein are preferably provided in unit dosageform. As used herein, a “unit dosage form” is a composition containingan amount of a compound that is suitable for administration to ananimal, preferably mammal subject, in a single dose, according to goodmedical practice. The preparation of a single or unit dosage formhowever, does not imply that the dosage form is administered once perday or once per course of therapy. Such dosage forms are contemplated tobe administered once, twice, thrice or more per day and may beadministered as infusion over a period of time (e.g., from about 30minutes to about 2-6 hours), or administered as a continuous infusion,and may be given more than once during a course of therapy, though asingle administration is not specifically excluded. The skilled artisanwill recognize that the formulation does not specifically contemplatethe entire course of therapy and such decisions are left for thoseskilled in the art of treatment rather than formulation.

The compositions useful as described above may be in any of a variety ofsuitable forms for a variety of routes for administration, for example,for oral, nasal, rectal, topical (including transdermal), ocular,intracerebral, intracranial, intrathecal, intra-arterial, intravenous,intramuscular, or other parental routes of administration. The skilledartisan will appreciate that oral and nasal compositions includecompositions that are administered by inhalation, and made usingavailable methodologies. Depending upon the particular route ofadministration desired, a variety of pharmaceutically-acceptablecarriers well-known in the art may be used. Pharmaceutically-acceptablecarriers include, for example, solid or liquid fillers, diluents,hydrotropies, surface-active agents, and encapsulating substances.Optional pharmaceutically-active materials may be included, which do notsubstantially interfere with the inhibitory activity of the compound.The amount of carrier employed in conjunction with the compound issufficient to provide a practical quantity of material foradministration per unit dose of the compound. Techniques andcompositions for making dosage forms useful in the methods describedherein are described in the following references, all incorporated byreference herein: Modern Pharmaceutics, 4th Ed., Chapters 9 and 10(Banker & Rhodes, editors, 2002); Lieberman et al., PharmaceuticalDosage Forms: Tablets (1989); and Ansel, Introduction to PharmaceuticalDosage Forms 8th Edition (2004).

Various oral dosage forms can be used, including such solid forms astablets, capsules, granules and bulk powders. Tablets can be compressed,tablet triturates, enteric-coated, sugar-coated, film-coated, ormultiple-compressed, containing suitable binders, lubricants, diluents,disintegrating agents, coloring agents, flavoring agents, flow-inducingagents, and melting agents. Liquid oral dosage forms include aqueoussolutions, emulsions, suspensions, solutions and/or suspensionsreconstituted from non-effervescent granules, and effervescentpreparations reconstituted from effervescent granules, containingsuitable solvents, preservatives, emulsifying agents, suspending agents,diluents, sweeteners, melting agents, coloring agents and flavoringagents.

The pharmaceutically-acceptable carriers suitable for the preparation ofunit dosage forms for peroral administration is well-known in the art.Tablets typically comprise conventional pharmaceutically-compatibleadjuvants as inert diluents, such as calcium carbonate, sodiumcarbonate, mannitol, lactose and cellulose; binders such as starch,gelatin and sucrose; disintegrants such as starch, alginic acid andcroscarmelose; lubricants such as magnesium stearate, stearic acid andtalc. Glidants such as silicon dioxide can be used to improve flowcharacteristics of the powder mixture. Coloring agents, such as the FD&Cdyes, can be added for appearance. Sweeteners and flavoring agents, suchas aspartame, saccharin, menthol, peppermint, and fruit flavors, areuseful adjuvants for chewable tablets. Capsules typically comprise oneor more solid diluents disclosed above. The selection of carriercomponents depends on secondary considerations like taste, cost, andshelf stability, which are not critical, and can be readily made by aperson skilled in the art.

Peroral compositions also include liquid solutions, emulsions,suspensions, and the like. The pharmaceutically-acceptable carrierssuitable for preparation of such compositions are well known in the art.Typical components of carriers for syrups, elixirs, emulsions andsuspensions include ethanol, glycerol, propylene glycol, polyethyleneglycol, liquid sucrose, sorbitol and water. For a suspension, typicalsuspending agents include methyl cellulose, sodium carboxymethylcellulose, AVICEL RC-591, tragacanth and sodium alginate; typicalwetting agents include lecithin and polysorbate 80; and typicalpreservatives include methyl paraben and sodium benzoate. Peroral liquidcompositions may also contain one or more components such as sweeteners,flavoring agents and colorants disclosed above.

Such compositions may also be coated by conventional methods, typicallywith pH or time-dependent coatings, such that the subject compound isreleased in the gastrointestinal tract in the vicinity of the desiredtopical application, or at various times to extend the desired action.Such dosage forms typically include, but are not limited to, one or moreof cellulose acetate phthalate, polyvinylacetate phthalate,hydroxypropyl methyl cellulose phthalate, ethyl cellulose, Eudragitcoatings, waxes and shellac.

Compositions described herein may optionally include other drug actives.

Other compositions useful for attaining systemic delivery of the subjectcompounds include sublingual, buccal and nasal dosage forms. Suchcompositions typically comprise one or more of soluble filler substancessuch as sucrose, sorbitol and mannitol; and binders such as acacia,microcrystalline cellulose, carboxymethyl cellulose and hydroxypropylmethyl cellulose. Glidants, lubricants, sweeteners, colorants,antioxidants and flavoring agents disclosed above may also be included.

A liquid composition, which is formulated for topical ophthalmic use, isformulated such that it can be administered topically to the eye. Thecomfort should be maximized as much as possible, although sometimesformulation considerations (e.g. drug stability) may necessitate lessthan optimal comfort. In the case that comfort cannot be maximized, theliquid should be formulated such that the liquid is tolerable to thepatient for topical ophthalmic use. Additionally, an ophthalmicallyacceptable liquid should either be packaged for single use, or contain apreservative to prevent contamination over multiple uses.

For ophthalmic application, solutions or medicaments are often preparedusing a physiological saline solution as a major vehicle. Ophthalmicsolutions should preferably be maintained at a comfortable pH with anappropriate buffer system. The formulations may also containconventional, pharmaceutically acceptable preservatives, stabilizers andsurfactants.

Preservatives that may be used in the pharmaceutical compositionsdisclosed herein include, but are not limited to, benzalkonium chloride,PHMB, chlorobutanol, thimerosal, phenylmercuric, acetate andphenylmercuric nitrate. A useful surfactant is, for example, Tween 80.Likewise, various useful vehicles may be used in the ophthalmicpreparations disclosed herein. These vehicles include, but are notlimited to, polyvinyl alcohol, povidone, hydroxypropyl methyl cellulose,poloxamers, carboxymethyl cellulose, hydroxyethyl cellulose and purifiedwater.

Tonicity adjustors may be added as needed or convenient. They include,but are not limited to, salts, particularly sodium chloride, potassiumchloride, mannitol and glycerin, or any other suitable ophthalmicallyacceptable tonicity adjustor.

Various buffers and means for adjusting pH may be used so long as theresulting preparation is ophthalmically acceptable. For manycompositions, the pH will be between 4 and 9. Accordingly, buffersinclude acetate buffers, citrate buffers, phosphate buffers and boratebuffers. Acids or bases may be used to adjust the pH of theseformulations as needed.

In a similar vein, an ophthalmically acceptable antioxidant includes,but is not limited to, sodium metabisulfite, sodium thiosulfate,acetylcysteine, butylated hydroxyanisole and butylated hydroxytoluene.

Other excipient components, which may be included in the ophthalmicpreparations, are chelating agents. A useful chelating agent is edetatedisodium, although other chelating agents may also be used in place orin conjunction with it.

For topical use, creams, ointments, gels, solutions or suspensions,etc., containing the compound disclosed herein are employed. Topicalformulations may generally be comprised of a pharmaceutical carrier,co-solvent, emulsifier, penetration enhancer, preservative system, andemollient.

For intravenous administration, the compounds and compositions describedherein may be dissolved or dispersed in a pharmaceutically acceptablediluent, such as a saline or dextrose solution. Suitable excipients maybe included to achieve the desired pH, including but not limited toNaOH, sodium carbonate, sodium acetate, HCl, and citric acid. In variousembodiments, the pH of the final composition ranges from 2 to 8, orpreferably from 4 to 7. Antioxidant excipients may include sodiumbisulfite, acetone sodium bisulfite, sodium formaldehyde, sulfoxylate,thiourea, and EDTA. Other non-limiting examples of suitable excipientsfound in the final intravenous composition may include sodium orpotassium phosphates, citric acid, tartaric acid, gelatin, andcarbohydrates such as dextrose, mannitol, and dextran. Furtheracceptable excipients are described in Powell, et al., Compendium ofExcipients for Parenteral Formulations, PDA J Pharm Sci and Tech 1998,52 238-311 and Nema et al., Excipients and Their Role in ApprovedInjectable Products: Current Usage and Future Directions, PDA J PharmSci and Tech 2011, 65 287-332, both of which are incorporated herein byreference in their entirety. Antimicrobial agents may also be includedto achieve a bacteriostatic or fungistatic solution, including but notlimited to phenylmercuric nitrate, thimerosal, benzethonium chloride,benzalkonium chloride, phenol, cresol, and chlorobutanol.

The compositions for intravenous administration may be provided tocaregivers in the form of one more solids that are reconstituted with asuitable diluent such as sterile water, saline or dextrose in watershortly prior to administration. In other embodiments, the compositionsare provided in solution ready to administer parenterally. In stillother embodiments, the compositions are provided in a solution that isfurther diluted prior to administration. In embodiments that includeadministering a combination of a compound described herein and anotheragent, the combination may be provided to caregivers as a mixture, orthe caregivers may mix the two agents prior to administration, or thetwo agents may be administered separately.

The actual dose of the active compounds described herein depends on thespecific compound, and on the condition to be treated; the selection ofthe appropriate dose is well within the knowledge of the skilledartisan.

Method of Treatment

Some embodiments described herein relate to a method of treating afibrotic condition, which can include administering a therapeuticallyeffective amount of a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof, to a subject. The methods include identifying asubject at risk for or having a fibrotic condition and administering acompound to the subject in an effective amount for therapeutic treatmentor prophylactic treatment of the fibrotic condition.

A “fibrotic condition,” “fibroproliferative condition,” “fibroticdisease,” “fibroproliferative disease,” “fibrotic disorder,” and“fibroproliferative disorder” are used interchangeably to refer to acondition, disease or disorder that is characterized by dysregulatedproliferation or activity of fibroblasts and/or abnormal accumulation offibronectin and/or pathologic or excessive accumulation of collagenoustissue. Typically, any such disease, disorder or condition is amenableto treatment by administration of a compound having anti-fibroticactivity. Fibrotic disorders include, but are not limited to, pulmonaryfibrosis, including idiopathic pulmonary fibrosis (IPF) and pulmonaryfibrosis from a known etiology, dermal fibrosis, pancreatic fibrosis,liver fibrosis (e.g., hepatic fibrosis associated with chronic activehepatitis), and renal fibrosis.

In some embodiments, the subject is a human.

The terms “therapeutically effective amount,” as used herein, refer toan amount of a compound sufficient to cure, ameliorate, slow progressionof, prevent, or reduce the likelihood of onset of the identified diseaseor condition, or to exhibit a detectable therapeutic, prophylactic, orinhibitory effect. The effect can be detected by, for example, theassays disclosed in the following examples. The precise effective amountfor a subject will depend upon the subject's body weight, size, andhealth; the nature and extent of the condition; and the therapeutic orcombination of therapeutics selected for administration. Therapeuticallyand prophylactically effective amounts for a given situation can bedetermined by routine experimentation that is within the skill andjudgment of the clinician.

For any compound, the therapeutically or prophylactically effectiveamount can be estimated initially either in cell culture assays, e.g.,of neoplastic cells, or in animal models, usually rats, mice, rabbits,dogs, or pigs. The animal model may also be used to determine theappropriate concentration range and route of administration. Suchinformation can then be used to determine useful doses and routes foradministration in humans.

Therapeutic/prophylactic efficacy and toxicity may be determined bystandard pharmaceutical procedures in cell cultures or experimentalanimals, e.g., ED₅₀ (the dose therapeutically effective in 50% of thepopulation) and LD₅₀ (the dose lethal to 50% of the population). Thedose ratio between therapeutic and toxic effects is the therapeuticindex, and it can be expressed as the ratio, ED₅₀/LD₅₀. Pharmaceuticalcompositions that exhibit large therapeutic indices are preferred.However, pharmaceutical compositions that exhibit narrow therapeuticindices are also within the scope of the invention. The data obtainedfrom cell culture assays and animal studies may be used in formulating arange of dosage for human use. The dosage contained in such compositionsis preferably within a range of circulating concentrations that includean ED₅₀ with little or no toxicity. The dosage may vary within thisrange depending upon the dosage form employed, sensitivity of thepatient, and the route of administration.

The exact dosage will be determined by the practitioner, in light offactors related to the subject that requires treatment. Dosage andadministration are adjusted to provide sufficient levels of the activeagent(s) or to maintain the desired effect. Factors which may be takeninto account include the severity of the disease state, general healthof the subject, age, weight, and gender of the subject, diet, time andfrequency of administration, drug combination(s), reactionsensitivities, and tolerance/response to therapy. Long-actingpharmaceutical compositions may be administered every 3 to 4 days, everyweek, or once every two weeks depending on half-life and clearance rateof the particular formulation.

In one aspect, treating a condition described herein results in anincrease in average survival time of a population of treated subjects incomparison to a population of untreated subjects. Preferably, theaverage survival time is increased by more than about 30 days; morepreferably, by more than about 60 days; more preferably, by more thanabout 90 days; and even more preferably by more than about 120 days. Anincrease in survival time of a population may be measured by anyreproducible means. In a preferred aspect, an increase in averagesurvival time of a population may be measured, for example, bycalculating for a population the average length of survival followinginitiation of treatment with an active compound. In an another preferredaspect, an increase in average survival time of a population may also bemeasured, for example, by calculating for a population the averagelength of survival following completion of a first round of treatmentwith an active compound.

In another aspect, treating a condition described herein results in adecrease in the mortality rate of a population of treated subjects incomparison to a population of subjects receiving carrier alone. Inanother aspect, treating a condition described herein results in adecrease in the mortality rate of a population of treated subjects incomparison to an untreated population. In a further aspect, treating acondition described herein results a decrease in the mortality rate of apopulation of treated subjects in comparison to a population receivingmonotherapy with a drug that is not a compound of the embodiments, or apharmaceutically acceptable salt, metabolite, analog or derivativethereof. Preferably, the mortality rate is decreased by more than about2%; more preferably, by more than about 5%; more preferably, by morethan about 10%; and most preferably, by more than about 25%. In apreferred aspect, a decrease in the mortality rate of a population oftreated subjects may be measured by any reproducible means. In anotherpreferred aspect, a decrease in the mortality rate of a population maybe measured, for example, by calculating for a population the averagenumber of disease-related deaths per unit time following initiation oftreatment with an active compound. In another preferred aspect, adecrease in the mortality rate of a population may also be measured, forexample, by calculating for a population the average number of diseaserelated deaths per unit time following completion of a first round oftreatment with an active compound.

In another aspect, treating a condition described herein results in areduction in the rate of cellular proliferation. Preferably, aftertreatment, the rate of cellular proliferation is reduced by at leastabout 5%; more preferably, by at least about 10%; more preferably, by atleast about 20%; more preferably, by at least about 30%; morepreferably, by at least about 40%; more preferably, by at least about50%; even more preferably, by at least about 60%; and most preferably,by at least about 75%. The rate of cellular proliferation may bemeasured by any reproducible means of measurement. In a preferredaspect, the rate of cellular proliferation is measured, for example, bymeasuring the number of dividing cells in a tissue sample per unit time.

In another aspect, treating a condition described herein results in areduction in the proportion of proliferating cells. Preferably, aftertreatment, the proportion of proliferating cells is reduced by at leastabout 5%; more preferably, by at least about 10%; more preferably, by atleast about 20%; more preferably, by at least about 30%; morepreferably, by at least about 40%; more preferably, by at least about50%; even more preferably, by at least about 60%; and most preferably,by at least about 75%. The proportion of proliferating cells may bemeasured by any reproducible means of measurement. In a preferredaspect, the proportion of proliferating cells is measured, for example,by quantifying the number of dividing cells relative to the number ofnondividing cells in a tissue sample. In another preferred aspect, theproportion of proliferating cells is equivalent to the mitotic index.

In another aspect, treating a condition described herein results in adecrease in size of an area or zone of cellular proliferation.Preferably, after treatment, size of an area or zone of cellularproliferation is reduced by at least 5% relative to its size prior totreatment; more preferably, reduced by at least about 10%; morepreferably, reduced by at least about 20%; more preferably, reduced byat least about 30%; more preferably, reduced by at least about 40%; morepreferably, reduced by at least about 50%; even more preferably, reducedby at least about 60%; and most preferably, reduced by at least about75%. Size of an area or zone of cellular proliferation may be measuredby any reproducible means of measurement. In a preferred aspect, size ofan area or zone of cellular proliferation may be measured as a diameteror width of an area or zone of cellular proliferation.

The methods described herein may include identifying a subject in needof treatment. In a preferred embodiment, the methods include identifyinga mammal in need of treatment. In a highly preferred embodiment, themethods include identifying a human in need of treatment. Identifying asubject in need of treatment may be accomplished by any means thatindicates a subject who may benefit from treatment. For example,identifying a subject in need of treatment may occur by clinicaldiagnosis, laboratory testing, or any other means known to one of skillin the art, including any combination of means for identification.

As described elsewhere herein, the compounds described herein may beformulated in pharmaceutical compositions, if desired, and can beadministered by any route that permits treatment of the disease orcondition. A preferred route of administration is oral administration.Administration may take the form of single dose administration, or thecompound of the embodiments can be administered over a period of time,either in divided doses or in a continuous-release formulation oradministration method (e.g., a pump). However the compounds of theembodiments are administered to the subject, the amounts of compoundadministered and the route of administration chosen should be selectedto permit efficacious treatment of the disease condition.

Further embodiments include administering a combination of compounds toa subject in need thereof. A combination can include a compound,composition, pharmaceutical composition described herein with anadditional medicament.

Some embodiments include co-administering a compound, composition,and/or pharmaceutical composition described herein, with an additionalmedicament. By “co-administration,”it is meant that the two or moreagents may be found in the patient's bloodstream at the same time,regardless of when or how they are actually administered. In someembodiments, the agents are administered simultaneously. In some suchembodiments, administration in combination is accomplished by combiningthe agents in a single dosage form. In some embodiments, the agents areadministered sequentially. In some embodiments the agents areadministered through the same route, such as orally. In some otherembodiments, the agents are administered through different routes, suchas one being administered orally and another being administered i.v.Thus, for example, the combination of active ingredients may be: (1)co-formulated and administered or delivered simultaneously in a combinedformulation; (2) delivered by alternation or in parallel as separateformulations; or (3) by any other combination therapy regimen known inthe art. When delivered in alternation therapy, the methods describedherein may comprise administering or delivering the active ingredientssequentially, e.g., in separate solution, emulsion, suspension, tablets,pills or capsules, or by different injections in separate syringes. Ingeneral, during alternation therapy, an effective dosage of each activeingredient is administered sequentially, i.e., serially, whereas insimultaneous therapy, effective dosages of two or more activeingredients are administered together. Various sequences of intermittentcombination therapy may also be used.

Pulmonary Fibrosis

Pulmonary fibrosis also called idiopathic pulmonary fibrosis (IPF),interstitial diffuse pulmonary fibrosis, inflammatory pulmonaryfibrosis, or fibrosing alveolitis, is a lung disorder and aheterogeneous group of conditions characterized by abnormal formation offibrous tissue between alveoli caused by alveolitis comprising cellularinfiltration into the alveolar septae with resulting fibrosis. Theeffects of IPF are chronic, progressive, and often fatal. The compoundsand methods described herein are useful in the treatment of pulmonaryfibrosis, such as IPF.

Renal Fibrosis

Irrespective of the nature of the initial insult, renal fibrosis isconsidered to be the common final pathway by which kidney diseaseprogresses to end-stage renal failure. The compounds and methodsdescribed herein are useful in the treatment of renal fibrosis.

Synthesis

The compounds disclosed herein may be synthesized by methods describedbelow, or by modification of these methods. Ways of modifying themethodology include, among others, temperature, solvent, reagents etc.,known to those skilled in the art. In general, during any of theprocesses for preparation of the compounds disclosed herein, it may benecessary and/or desirable to protect sensitive or reactive groups onany of the molecules concerned. This may be achieved by means ofconventional protecting groups, such as those described in ProtectiveGroups in Organic Chemistry (ed. J. F. W. McOmie, Plenum Press, 1973);and P. G. M. Green, T. W. Wutts, Protecting Groups in Organic Synthesis(3rd ed.) Wiley, New York (1999), which are both hereby incorporatedherein by reference in their entirety. The protecting groups may beremoved at a convenient subsequent stage using methods known from theart. Synthetic chemistry transformations useful in synthesizingapplicable compounds are known in the art and include e.g. thosedescribed in R. Larock, Comprehensive Organic Transformations, VCHPublishers, 1989, or L. Paquette, ed., Encyclopedia of Reagents forOrganic Synthesis, John Wiley and Sons, 1995, which are both herebyincorporated herein by reference in their entirety. The routes shown anddescribed herein are illustrative only and are not intended, nor arethey to be construed, to limit the scope of the claims in any mannerwhatsoever. Those skilled in the art will be able to recognizemodifications of the disclosed syntheses and to devise alternate routesbased on the disclosures herein; all such modifications and alternateroutes are within the scope of the claims.

EXAMPLES

Additional embodiments are disclosed in further detail in the followingexamples, which are not in any way intended to limit the scope of theclaims.

Example 1-A Synthesis of Compound 1 (Scheme I)

To a solution of ethyl thioglycolate (11.14 g, 92.8 mmol) in 400 mL ofDMF was added NaOEt (14.5 g, 185.7 mmol) by portion wise. The resultingmixture was stirred for 30 min at 0° C. And then I-1 (10 g, 71.4 mmol)was added to the solution by portion wise. The mixture was stirred at120° C. overnight. The reaction mixture was cooled to it, diluted withwater (300 mL), extracted with EtOAc (300 mL×3), the combined organiclayers were washed with brine, dried over anhydrous Na₂SO₄ andconcentrated. The residue was washed with petroleum ether to afford I-2(8.7 g, 59% yield) as a pale brown solid. ¹H NMR (CDCl₃, 400 MHz) δ 8.68(dd, J=1.6, 4.4 Hz, 1H), 8.16 (dd, J=1.6, 8.0 Hz, 1H), 8.00 (s, 1H),7.36 (m, 1H), 4.43 (q, J=7.2 Hz, 2H), 1.42 (t, J=7.2 Hz, 3H). MS (ESI)m/z [M+H]⁺ 208.0.

To a solution of I-2 (7.5 g, 36.2 mmol) in 300 mL of DCM was addedm-CPBA (12.4 g, 72.4 mmol) by portion wise at 0° C. The resultingsolution was stirred at rt overnight, followed by quench with saturatedaq.Na₂S₂O₃. The organic layer was separated, the aqueous layer wasextracted with EtOAc (200 mL×3). The combined organic layers were washedwith saturated aq. NaHCO₃ and brine, dried over anhydrous Na₂SO₄ andconcentrated. The crude product was washed with petroleum ether toproduce I-3 (7.5 g, 93% yield) as a white solid. MS (ESI) m/z [M+H]⁺224.0.

I-3 (7.0 g, 31.4 mmol) was added into 60 mL of Ac₂O, the solution washeated to reflux overnight. The reaction mixture was concentrated, theresidue was dissolved with 100 mL of MeOH, and 6 mL of TEA was addedthereto, the mixture was stirred at rt for 4 hours, and then it wasconcentrated, diluted with EtOAc (500 mL), washed with water and brine,dried over anhydrous Na₂SO₄ and concentrated. The residue was purifiedby flash chromatography on silica gel with petroleum ether/EtOAc(20:1→10:1→5:1→1:1→1:2→1:10) to afford I-4 (2.8 g, 40% yield) as a brownsolid. MS (ESI) m/z [M+H]⁺ 223.8.

A flask was charged with I-4 (1.0 g, 4.48 mmol), 4-chlorophenyl boronicacid (2.11 g, 13.45 mmol), Cu(OAc)₂ (4.05 g, 22.4 mmol), pyridineN-oxide (4.26 g, 44.8 mmol), pyridine (2.69 g, 35.8 mmol), 4 Å molecularsieve (1.0 g) and 300 mL of anhydrous DCM. The mixture was stirred underoxygen atmosphere at rt. overnight. The reaction was monitored by TLC,when the starting material was consumed, the mixture was concentrated,diluted with water (100 mL), extracted with EtOAc (300 mL×3). Thecombined organic layer was washed with brine, dried over anhydrousNa₂SO₄ and concentrated. The residue was purified by flashchromatography on silica gel with petroleum ether/EtOAc(50:1→30:1→10:1→5:1→2:1) to afford Compound 1 (900 mg, 60% yield) as apale yellow solid. ¹H NMR (DMSO-d₆, 400 MHz) δ 8.04-8.00 (m, 2H), 7.71(d, J=8.4 Hz, 2H), 7.60 (d, J=8.4 Hz, 2H), 6.60 (d, J=9.6 Hz, 1H), 4.24(q, J=7.2 Hz, 2H), 1.24 (t, J=7.2 Hz, 3H). MS (ESI) m/z [M+H]⁺ 333.9.

Compound 2 was prepared following the procedure for obtaining Compound 1using 1-(2-chloropyridin-3-yl)ethanone in place of I-1 as a white solid.¹H NMR (CD₃OD, 400 MHz) δ 8.06 (d, J=9.2 Hz, 1H), 7.70-7.67 (m, 2H),7.50-7.48 (m, 2H), 6.68 (d, J=9.6 Hz, 1H), 4.29 (q, J=7.2 Hz, 2H), 2.69(s, 3H), 1.35 (t, J=7.2 Hz, 3H). MS (ESI) m/z (M+H)⁺ 347.9.

Example 1-B Synthesis of Compound 3 (Scheme II)

NaH (1.29 g, 54 mmol) was added to the stirred mixture of II-1 (5.0 g,27 mmol) and ethyl thioglycolate (3.9 g, 32.4 mmol) in DMF (50 mL) at 0°C. The reaction mixture was stirred at rt overnight. The reaction wasslowly quenched with water (50 mL) and then extracted with EtOAc (50mL×3). The combined organic layer was washed with brine, dried overNa₂SO₄, and concentrated to afford the crude II-2 (3.7 g, 51% crudeyield), which was used for next step directly.

NaOEt (1.87 g, 27.4 mmol) was added to the mixture of II-2 (3.7 g, 13.7mmol) in 30 mL of EtOH, and the reaction mixture was stirred at rt for 2hours. Then the mixture was adjusted to pH=2 with aq. HCl (2 M), theprecipitated solid was collect to afford II-3 (2.4 g, 79% yield), whichwas used for next step directly.

A mixture of II-3 (3 g, 13.4 mmol) and NaOAc (2.2 g, 26.8 mmol) in Ac₂O(50 ml) was stirred at reflux for 2 hours. The mixture was cooled tort., concentrated in vacuo, the mixture was dissolved in EtOAc (100 mL),washed with saturated aq. Na₂CO₃ and water. The organic phase was driedover Na₂SO₄, concentrated under reduced pressure to give II-4 (3 g, 84%yield).

To a stirring solution of II-4 (3 g, 11.3 mmol) in anhydrous DCM (60 mL)at 0° C. was added m-CPBA (5.85 g, 34 mmol). Then the mixture wasstirred overnight at rt. After that the mixture was washed withsaturated aq. Na₂SO₃ solution, dried over Na₂SO₄ and concentrated underreduced pressure. The residue was re-crystallized from EtOAc to produceII-5 (2.5 g, 79% yield) as white solid.

II-5 (2.5 g, 8.9 mmol) was dissolved in Ac₂O (30 mL) and the mixture wasrefluxed at 140° C. for 18 hrs. After being cooled to rt, the mixturewas concentrated under reduced pressure. The residue was purified bycolumn chromatography on silica gel with petroleum ether/EtOAc (20:1) togive a mixture of II-6 and II-6A (1.5 g, 52% yield) as yellow solid.

To a stirring solution of mixture II-6 and II-6A (1.3 g, 4 mmol) in MeOH(65 mL) was added TEA (10 mL) at rt. Then the mixture was stirred for 1h at ambient temperature. The mixture was concentrated under reducedpressure to afford a mixture of II-7 and II-7A (1.0 g, 88% crude yield)as yellow solid, which was used directly without further purification.

A mixture of II-7 and II-7A (500 mg, 1.8 mmol), 4-chlorophenyl boronicacid (842 mg, 5.4 mmol), Cu(OAc)₂ (1.63 g, 9 mmol), pyridine-N-oxide(1.71 g, 18 mmol) and pyridine (1.42 g, 18 mmol) in anhydrous DCM (50mL) was stirred for 80 hours at rt under air. Then the mixture waswashed with water and the organic phase was dried over Na₂SO₄,concentrated under reduced pressure. The residue was purified byPrep-HPLC to give Compound 3 (100 mg, 16% yield). ¹H NMR (CD₃OD, 400MHz) δ 7.96 (d, J=9.2 Hz, 1H), 7.62 (d, J=8.4 Hz, 2H), 7.41 (d, J=8.4Hz, 2H), 6.43 (d, J=9.2 Hz, 1H), 4.15 (q, J=7.2 Hz, 2H), 1.24 (t, J=7.2Hz, 3H). MS (ESI) m/z (M+H)⁺ : 349.9.

Compound 4 was prepared following the similar procedure for obtainingCompound 3 using 1-(2-chloropyridin-3-yl)propan-1-one in place of II-1.¹H NMR (DMSO-d₆, 400 MHz) δ 12.3 (brs, 1H), 8.03 (d, J=9.6 Hz, 1H), 6.53(d, J=9.2 Hz, 1H), 4.29 (q, J=7.2 Hz, 2H), 3.12 (q, J=7.2 Hz, 2H), 1.33(t, J=7.2 Hz, 3H), 1.15 (t, J=7.2 Hz, 3H).

Example 2 Synthesis of 5-Acyl Pirfenidone Analogs (Scheme III)

To a solution of III-1 (30 g, 0.162 mol, 1 eq.) in 300 mL of anhydrousTHF was added dropwise a solution of n-BuLi (2.5M in hexane, 77.5 mL,0.19 mol, 1.2 eq.) at −70° C. After completion of addition, the mixturewas stirred at −70° C. for 20 min, followed by addition of a solution ofN-methoxy-N-methylacetamide (33 g, 0.322 mol, 2 eq.) in 100 mL ofanhydrous THF by drop wise, the solution was allowed to warm to rt andstirred for 2 hrs. The reaction was quenched with saturated aq. NH₄Cl(100 mL), extracted with EtOAc (300 mL×3), the organic layer was washedwith brine, dried over anhydrous Na₂SO₄, and concentrated in vacuo. Theresidue was purified by flash chromatography on silica gel withpetroleum ether/EtOAc (100:1) to yield III-2 (14.8 g, 62% yield) as awhite solid. ¹H NMR (DMSO-d₆, 400 MHz) δ 8.81 (d, J=2.0 Hz, 1H), 8.16(dd, J=2.4, 8.4 Hz, 1H), 6.90 (d, J=8.8 Hz, 1H), 3.93 (s, 3H), 2.55 (s,3H). MS (ESI) m/z [M+H]⁺ 151.6.

To a solution of III-2 (5 g, 33 mmol) in 20 mL of EtOH was added aq. HBr(48%, 60 mL), the reaction mixture was heated to reflux overnight. Afterbeing cooled to rt., the mixture was neutralized by addition ofsaturated aq. NaHCO₃, extracted with EtOAc (100 mL×3). The combinedorganic layer was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated to supply crude III-3 (3 g, 65% yield) as white solid.

To a solution of III-3 (1 eq.) in DCM (0.1 mmol/mL) was added boronicacid III-4 (2 eq.), Cu(OAc)₂ (1 eq), Pyridine (10 eq.) andPyridine-N-Oxide (2 eq.), followed by addition of 4 Å molecular sieve(quantity approx. equal to III-3). The reaction mixture was stirred atrt under oxygen atmosphere overnight. After completion of the reactionindicated by TLC, the resulting mixture was filtered and washed with,the filtrate was washed with brine, dried over Na₂SO₄ and concentrated.The residue was purified by column chromatography on silica gel to giveIII-5.

Compound 10 (61% yield): ¹H NMR (DMSO-d₆, 400 MHz) δ 8.43 (d, J=2.4 Hz,1H), 7.90 (dd, J=9.6, 2.4 Hz, 1H), 7.39 (d, J=8.8 Hz, 2H), 7.06 (d,J=8.8 Hz, 2H), 6.51 (d, J=9.6 Hz, 1H), 3.81 (s, 3H), 2.41 (s, 3H).

Compound 11 (67% yield): ¹H NMR (DMSO-d₆, 300 MHz) δ 8.42 (d, J=2.4 Hz,1H), 7.88 (dd, J=9.6, 2.4 Hz, 1H), 7.34 (d, J=8.7 Hz, 2H), 7.02 (d,J=9.0 Hz, 2H), 6.49 (d, J=9.6 Hz, 1H), 4.68-4.64 (m, 1H), 3.40 (s, 3H),1.28 (s, 3H), 1.26 (s, 3H).

Compound 12 (50% yield): ¹H NMR (DMSO-d₆, 400 MHz) δ 8.57 (d, J=2.4 Hz,1H), 7.95-7.92 (m, 2H), 7.87 (d, J=7.6 Hz, 1H), 7.82-7.79 (m, 2H), 6.56(d, J=9.6 Hz, 1H), 2.43 (s, 3H).

Compound 13 (78% yield): ¹H NMR (DMSO-d₆, 400 MHz) δ 8.52 (d, J=2.4 Hz,1H), 7.95-7.91 (m, 1H), 7.64 (d, J=8.8 Hz, 2H), 7.56 (d, J=8.8 Hz, 2H),6.56 (d, J=9.6 Hz, 1H), 2.44 (s, 3H).

Compound 14 (74% yield): ¹H NMR (DMSO-d₆, 400 MHz) δ 8.49 (d, J=2.4 Hz,1H), 7.91 (dd, J=9.6, 2.4 Hz, 1H), 7.56-7.52 (m, 2H), 7.40-7.35 (m, 2H),6.53 (d, J=9.6 Hz, 1H), 2.42 (s, 3H).

Compound 15 (67% yield): ¹H NMR (DMSO-d₆, 400 MHz) δ 8.45 (d, J=2.4 Hz,1H), 7.90 (dd, J=9.6, 2.8 Hz, 1H), 7.46-7.41 (m, 1H), 7.03 (t, 3H), 6.52(d, J=9.6 Hz, 1H), 3.79 (s, 3H), 2.42 (s, 3H).

Compound 16 (74% yield): ¹H NMR (DMSO-d₆, 400 MHz) δ 8.53 (d, J=2.8 Hz,1H), 7.90 (dd, J=9.6, 2.4 Hz, 1H), 7.64-7.58 (m, 1H), 7.52-7.48 (m, 1H),7.41-7.35 (m, 2H), 6.57 (d, J=9.6 Hz, 2H), 2.45 (s, 3H).

Compound 17 (64% yield): ¹H NMR (DMSO-d₆, 400 MHz) δ 8.55 (d, J=2.4 Hz,1H), 7.92 (dd, J=9.6, 2.4 Hz, 1H), 7.67-7.63 (m, 2H), 7.55 (d, J=8.4 Hz,2H), 6.56 (d, J=9.6 Hz, 1H), 2.42 (s, 3H).

Compound 18 (23% yield): ¹H NMR (DMSO-d₆, 400 MHz) δ 8.37 (d, J=2.4 Hz,1H), 7.92 (dd, J=9.6, 2.4 Hz, 1H), 7.20 (d, J=8.4 Hz, 1H), 6.95 (d,J=2.8 Hz, 1H), 6.52 (d, J=9.6 Hz, 1H), 4.06 (q, J=6.8 Hz, 2H), 2.40 (s,3H), 2.00 (s, 3H), 1.34 (t, J=6.8 Hz, 3H).

Compound 19 (40% yield): ¹H NMR (DMSO-d₆, 400 MHz) δ 10.18 (s, 1H), 8.46(d, J=2.4 Hz, 1H), 7.91 (dd, J=9.6, 2.4 Hz, 1H), 7.73 (s, 1H), 7.60 (d,J=8.4 Hz, 1H), 7.46 (t, J=8.0 Hz, 1H), 7.12 (dd, J=7.6, 0.8 Hz, 1H),6.53 (d, J=9.6 Hz, 1H), 2.41 (s, 3H), 2.05 (s, 3H).

Compound 20 was prepared following the general procedure, except thesolvent was changed to acetonitrile (10% yield). ¹H NMR (CDCl₃, 400 MHz)δ 8.06 (d, J=2.4 Hz, 1H), 7.97 (dd, J=10, 2.4 Hz, 1H), 7.53-7.45 (m,1H), 7.43-7.36 (m, 1H), 7.34-7.25 (m, 2H), 6.67 (d, J=10 Hz, 1H), 2.45(s, 3H). MS (ESI) m/z (M+H)⁺ 232.0.

Example 3-A Synthesis of Compound 21 (Scheme IV)

To a solution of 5-methyl-2-pyridone IV-1 (643 mg, 5.9 mmol) in DCM (71mL) and DMF (23.5 mL), Cu(OAc)₂ (2.14 g, 11.784 mmol), 4-hydroxy phenylboronic acid (0.975 g, 7.07 mmol), pyridine (0.95 mL, 11.784 mmol) andactivated 4 Å molecular sieves (7.1 g) were added. The mixture wasstirred at rt for 24 hours. A concentrated solution of NH₄OH was added,filtered through celite. Filtrate was evaporated under vacuum, and theresulting crude was purified by flash chromatography (SiO₂, DCM/MeOH) toafford IV-2, 600 mg (51% yield) of pure product as pale yellow solid.MS: m/z 202.2 (M+H).

To a suspension of IV-2 (250 mg, 1.24 mmol) in DMF (9 mL) was addedPEG-Tos (395 mg, 1.24 mmol), K₂CO₃ (343 mg, 2.48 mmol) and heated at 50°C. for 24 hours. Reaction mixture was filtered through a celite pad,washed with MeOH and solvents were removed under vacuum. The crudematerial was purified by flash chromatography (SiO₂, DCM/MeOH) to affordCompound 21 (400 mg, 93% yield) of pure product as colorless oil. MS:m/z 348.4 (M+H).

Compound 22 was prepared following the similar procedure for obtainingCompound 21 using 1-(3-hydroxyphenyl)-5-methylpyridin-2(1H)-one in placeof IV-2. MS: m/z=348.6 (M+H).

Example 3-B Synthesis of Compound 23 (Scheme V)

A mixture of V-1 (4.3 g, 22 mmol), boronic acid V-2 (2.75 g, 14 mmol),pyridine (3.58 mL, 43.9 mmol), pyridine N-oxide (4.2 g, 43.9 mmol), 4 Åmolecular sieve (300 mg) and Cu(OAc)₂ (7.95 g, 43.9 mmol) in anhydrousDCM (200 mL) was degassed by purging with O₂. The reaction mixture wasstirred at r.t. for 12 hours. The suspension was filtered and filtratewas washed with brine, dried over anhydrous Na₂SO₄, and concentrated invacuo. The residue was purified by flash chromatography on silica gelwith PE/EtOAc (10:1→2:1) to give V-3 (1.76 g, 36% yield). ¹H NMR (CDCl₃,300 MHz) δ 7.48 (s, 1H), 7.26-7.23 (m, 2H), 7.01-6.98 (m, 2H), 6.54 (s,1H), 4.14 (t, J=4.8 Hz, 2H), 3.76 (t, J=4.8 Hz, 2H), 3.45 (s, 3H), 2.27(s, 3H).

To a solution of V-3 (510 mg, 1.51 mmol) in 12 mL of DME/H₂O (v/v=5/1)was added Na₂CO₃ (320 mg, 3.02 mmol), V-4 (317 mg, 2.26 mmol),Pd(dppf)Cl₂ (110 mg, 0.15 mmol). The mixture was purged with nitrogenand then heated at reflux overnight. The mixture was cooled to r.t.,diluted with water (30 mL), extracted with EtOAc (100 mL×3). Thecombined organic layer was washed with brine, dried over anhydrousNa₂SO₄, and concentrated in vacuo. The residue was purified by flashchromatography on silica gel with PE/EtOAc (10:1→1:1) to produceCompound 23 (300 mg, 56% yield) as a yellow oil. ¹H NMR (CDCl₃, 400 MHz)δ 7.33-7.30 (m, 2H), 7.25-7.23 (m, 2H), 7.17 (s, 1H), 7.11-7.07 (m, 2H),7.02-7.00 (m, 2H), 6.56 (s, 1H), 4.15 (t, J=4.8 Hz, 2H), 3.76 (t, J=4.8Hz, 2H), 3.45 (s, 3H), 2.12 (s, 3H).

Compound 24 was prepared following the similar procedure for obtainingCompound 23 using tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylatein place of V-4 as a yellow oil. ¹H NMR (CDCl₃, 400 MHz) δ 7.58 (s, 2H),7.30 (d, J=8.8 Hz 2H), 7.26 (s, 1H), 7.01 (d, J=8.8 Hz, 2H), 6.58 (s,1H), 4.15 (t, J=4.8 Hz, 2H), 3.76 (t, J=4.8 Hz, 2H), 3.46 (s, 3H), 2.21(s, 3H).

Compound 25 was prepared following the similar procedure for obtainingCompound 23 using1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole inplace of V-4 as a yellow oil. ¹H NMR (CDCl₃, 400 MHz) δ 7.47 (s, 1H),7.36 (s, 1H), 7.31-7.22 (m, 3H), 7.03-6.98 (m, 2H), 6.55 (s, 1H), 4.14(t, J=4.8 Hz, 2H), 3.93 (s, 3H), 3.76 (t, J=4.8 Hz, 2H), 3.46 (s, 3H),2.21 (s, 3H).

Example 3-C Synthesis of Compound 26 (Scheme VI)

To a stirred mixture of VI-1 (600 mg, 2.97 mmol), phenyl boronic acid(435 mg, 3.56 mmol), and K₃CO₃ (409 mg, 8.91 mmol) in DME/H₂O (22 mL,v/v=10/1) was added Pd(dppf)Cl₂ (436 mg, 0.594 mmol). The mixture waspurged with nitrogen for three times and then heated at 100° C.overnight. The mixture was concentrated to remove DME, diluted with H₂O(50 mL), extracted with EtOAc (100 mL×3). The combined organic layer waswashed with water and brine, dried over anhydrous Na₂SO₄, andconcentrated in vacuo. The crude product was purified by prep-TLC(PE/EA=5/1) to give VI-2 (226 mg, 38% yield).

A mixture of VI-2 (226 mg, 1.13 mmol) with aq. HBr (48%, 10 mL) washeated to reflux under nitrogen overnight. After being cooled to r.t.,the mixture was neutralized by adding saturated aq. NaHCO₃, and thenextracted with EtOAc (80 mL×3). The combined organic layer was washedwith water and brine, dried over anhydrous Na₂SO₄, and concentrated invacuo to afford VI-3 (180 mg, 85% yield).

To a stirred mixture of VI-3 (180 mg, 0.972 mmol), boronic acid VI-4(285 mg, 1.46 mmol), copper (II) acetate (528 mg, 2.92 mmol) andpyridine (231 mg, 2.92 mmol) in DCM (10 mL) was added pyridine-N-oxide(277 mg, 2.92 mmol) in one portion. The solution was stirred at r.t.under oxygen atmosphere overnight. After completion of the reactionindicated by TLC, the resulting mixture was concentrated in vacuo.Dissolved the residue in ethyl acetate (100 mL), filtered, and washedthe filtrate with brine. The organic phase was dried over anhydroussodium sulfate, filtered, concentrated in vacuo to afford a yellowishsolid. The crude product was purified by prep-HPLC to give Compound 26(48.8 mg, 15% yield) as a yellow solid. ¹H NMR (CDCl₃, 400 MHz) δ7.42-7.28 (m, 7H), 7.20 (s, 1H), 7.00 (d, J=8.8 Hz, 2H), 6.57 (s, 1H),4.14 (t, J=4.8 Hz, 2H), 3.76 (t, J=4.8 Hz, 2H), 3.46 (s, 3H), 2.15 (s,3H).

Example 4 Synthesis of Compound 27 (Scheme VII)

VII-1 (2 g, 20 mmol) was added dropwise to ammonia (7 mL) at −70° C. Thereaction mixture was stirred at −70° C. for 1 hour, and then thereaction mixture was warmed to rt for one additional hour. The organiclayer was separated and evaporated to produce VII-2, which was useddirectly for next step.

A mixture of VII-2 (0.69 g, 10 mmol), VII-3 (1.56 g, 10 mmol), andNa₂CO₃ (1.06 g, 10 mmol) in water (25 ml) was stirred at rt overnight.And then the mixture was extracted with EtOAc (50 mL×3). The combinedorganic layer was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated. The residue was purified by flash chromatography on silicagel with PE/EtOAc (4/1) to yield VII-4 (0.55 g, 24% yield). ¹H NMR(CDCl₃, 400 MHz) δ 7.13 (s, 1H), 6.63 (d, J=10 Hz, 1H), 5.88 (d, J=10Hz, 1H), 5.39 (brs, 1H), 4.24-4.15 (m, 2H), 2.50-2.42 (m, 1H), 2.33-2.25(m, 1H), 2.02-1.95 (m, 1H), 1.92-1.80 (m, 2H), 1.76-1.66 (m, 1H),1.27-1.18 (m, 3H).

A solution of VII-4 (1.13 g, 5 mmol) in conc. HCl (30 mL) was stirred ina sealed tube at 110° C. overnight. The solvent was evaporated undervacuum to yield crude VII-5 (0.95 g, 111% crude yield). ¹H NMR (DMSO-d₆,400 MHz) δ 7.85 (d, J=8.8 Hz, 1H), 6.82 (d, J=8.8 Hz, 1H), 2.93-2.80 (m,2H), 2.78-2.72 (m, 2H), 2.13-2.02 (m, 2H).

To a mixture of VII-5 (0.513 g, 3 mmol) and phenyl boronic acid VII-6(0.732 g, 6 mmol) in acetonitrile (30 mL) was added Cu(OAc)₂ (1.64 g, 9mmol), pyridine (1.42 g, 18 mmol) and pyridine-N-oxide (0.86 g, 9 mmol).The mixture was stirred under oxygen atmosphere at rt overnight. Themixture was diluted with water (50 mL) and extracted with CH₂Cl₂ (50mL×3). The combined organic layer was washed with brine, dried overNa₂SO₄, and concentrated under reduced pressure. The residue waspurified by column chromatography on silica gel with petroleumether/EtOAc (8:1˜1:1) to afford Compound 27 (0.38 g, 60% yield). ¹H NMR(CDCl₃, 400 MHz) δ 7.51-7.41 (m, 3H), 7.33-7.31 (m, 1H), 7.25-7.22 (m,2H), 6.51 (d, J=9.2 Hz, 1H), 2.81-2.77 (m, 2H), 2.50-2.46 (m, 2H),2.07-2.00 (m, 2H). MS (ESI) m/z (M+H)⁺ 212.0.

Compound 28 was prepared following the similar procedure for obtainingCompound 27 using (4-(trifluoromethoxy)phenyl)boronic acid in place ofphenyl boronic acid (VII-6). ¹H NMR: (CDCl₃, 400 MHz) δ 7.37-7.26 (m,5H), 6.50 (d, J=9.2 Hz, 1H), 2.81-2.77 (m, 2H), 2.51-2.47 (m, 2H),2.09-2.02 (m, 2H). MS (ESI) m/z (M+H)⁺ 295.9.

Example 5-A Synthesis of Compound 29 (Scheme VIII)

An autoclave was charged with VIII-1 (4.0 g, 27.6 mmol), PtO₂ (400 mg)and 50 mL of TFA. The mixture was stirred at 110° C. under hydrogen(pressure 2.0 MPa) for 1 day, then the solution was filtered, and thesolid was washed with MeOH. The filtrate was concentrated under reducedpressure. The resulting residue was purified by column chromatography onsilica gel with petroleum ether/EtOAc (10:1→5:1→1:1→1:5→EtOAc) to giveVIII-2 (2.1 g, 51% yield) as white solid. ¹H NMR (CDCl₃, 400 MHz) δ12.85 (brs, 1H), 7.16 (d, J=6.4 Hz, 1H), 6.02 (d, J=6.4 Hz, 1H),2.60-2.50 (m, 4H), 1.81-1.71 (m, 4H). MS (ESI) m/z [M+H]⁺ 149.8.

To a solution of VIII-2 (1.04 g, 7 mmol) in CHCl₃ (20 mL) was added Br₂(1.12 g, 7 mmol) dropwise at 0° C. The reaction mixture was stirred atrt for 2 hrs. And then the reaction mixture was poured into ice-water,and the solid formed was collected by filtration, the filtrate wasextracted with EtOAc (50 mL×3), the solid was re-dissolved in EtOAc (40mL). The combined organic layer was washed with brine, dried over Na₂SO₄and concentrated under reduced pressure to afford crude VIII-3 (1.3 g,61% yield). ¹H NMR (CDCl₃, 300 MHz) δ 7.44 (s, 1H), 2.62-2.52 (m, 4H),1.81-1.72 (m, 4H). MS (ESI) m/z [M+H]⁺ 227.

VIII-3 (500 mg, 2.2 mmol, 1.0 eq.), VIII-4 (405 mg, 3.3 mmol, 1.5 eq.),Cu(OAc)₂ (1.2 g, 6.6 mmol, 3 eq.), pyridine-N-oxide (630 mg, 6.6 mmol, 3eq.) and pyridine (520 mg, 6.6 mmol, 3 eq.) and 4 Å molecular sieve (500mg) was added into 150 mL of anhydrous DCM. The mixture was stirredunder oxygen atmosphere at r.t. overnight. The reaction mixture wasfiltered; the combined organic layer was washed with brine, dried overNa₂SO₄, and concentrated. The resulting residue was re-crystallized fromEtOAc to yield VIII-5 (550 mg, 83% yield). ¹H NMR (CDCl₃, 300 MHz) δ7.49-7.30 (m, 6H), 2.64-2.58 (m, 4H), 1.81-1.72 (m, 4H). MS (ESI) m/z(M+H)⁺ 303.9.

A flask was charged with VIII-5 (300 mg, 1 mmol, 1 eq.), MeB(OH)₂ (240mg, 4.0 mmol, 4 eq.), and Na₂CO₃ (418 mg, 3.0 mmol, 3 eq.) in DME/H₂O(24 mL, V/V=5/1). It was purged with N₂, and then Pd(PPh₃)₄ (115 mg, 0.1mmol, 0.1 eq.) was added. The reaction mixture was purged with N₂ againand then stirred at 110° C. overnight. The mixture was concentratedunder reduced pressure to remove the solvent, and then it was dilutedwith H₂O (30 mL), extracted with EtOAc (30 mL×3), the combined organiclayer was washed with brine, dried over Na₂SO₄, and concentrated invacuo. The residue was purified by prep-TLC (PE: EA=2.5:1) to giveCompound 29 (190 mg, 79% yield) as white solid. ¹H NMR (CDCl₃, 400 MHz)δ 7.47-7.42 (m, 2H), 7.39-7.35 (m, 3H), 6.99 (s, 1H), 2.61-2.58 (m, 2H),2.52-2.50 (m, 2H), 2.00 (s, 3H), 1.81-1.75 (m, 4H). MS (ESI) m/z [M+H]⁺240.1.

Compound 30 was prepared following the similar procedure for obtainingCompound 29 using (4-fluorophenyl)boronic acid in place of methylboronic acid (VIII-6) as a white solid. ¹H NMR (CDCl₃, 400 MHz) δ7.48-7.37 (m, 5H), 7.26-7.23 (m, 2H), 7.10-7.06 (m, 3H), 2.68-2.64 (m,2H), 2.40-2.37 (m, 2H), 1.81-1.77 (m, 2H), 1.72-1.68 (m, 2H). MS (ESI)m/z [M+H]⁺ 320.0.

Compound 31 was prepared following the similar procedure for obtainingCompound 29 using1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole inplace of methyl boronic acid (VIII-6). ¹H NMR (CDCl₃, 400 MHz) δ7.49-7.45 (m, 3H), 7.41-7.39 (m, 3H), 7.34 (s, 1H), 7.15 (s, 1H), 3.93(s, 3H), 2.65-2.62 (m, 2H), 2.55-2.52 (m, 2H), 1.80-1.72 (m, 4H). MS(ESI) m/z [M+H]⁺ 306.2.

Compound 32 was prepared following the similar procedure for obtainingCompound 30 using (4-(trifluoromethoxy)phenyl)boronic acid in place ofphenyl boronic acid (VIII-4). ¹H NMR (CDCl₃, 400 MHz) δ 7.49-7.45 (m,2H), 7.31 (d, J=8.4 Hz, 2H), 7.26-7.22 (m, 2H), 7.11-7.06 (m, 3H),2.66-2.63 (m, 2H), 2.40-2.37 (m, 2H), 1.81-1.74 (m, 2H), 1.72-1.67 (m,2H). MS (ESI) m/z [M+H]⁺ 404.2.

Compound 33 was prepared following the similar procedure for obtainingCompound 31 using (4-(trifluoromethoxy)phenyl)boronic acid in place ofphenyl boronic acid (VIII-4). ¹H NMR (CDCl₃, 400 MHz) δ 7.46-7.43 (m,3H), 7.34-7.30 (m, 3H), 7.17 (s, 1H), 3.94 (s, 3H), 2.64-2.61 (m, 2H),2.54-2.51 (m, 2H), 1.81-1.72 (m, 4H). MS (ESI) m/z [M+H]⁺ 390.2.

Compound 34 was prepared following the similar procedure for obtainingCompound 30 using (4-(trifluoromethoxy)phenyl)boronic acid in place ofphenyl boronic acid (VIII-4) and (4-fluorophenyl)boronic acid in placeof methyl boronic acid (VIII-6). ¹H NMR (CDCl₃, 400 MHz) δ 7.48-7.45 (m,2H), 7.44-7.30 (m, 3H), 7.10-6.97 (m, 4H), 2.64 (t, J=6.0 Hz, 2H), 2.41(t, J=6.0 Hz, 2H), 1.82-1.76 (m, 2H), 1.72-1.66 (m, 2H). MS (ESI) m/z[M+H]⁺ 404.0.

Compound 35 was prepared following the similar procedure for obtainingCompound 29 using (4-ethoxy-2-methylphenyl)boronic acid in place ofphenyl boronic acid (VIII-4) and1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole inplace of methyl boronic acid (VIII-6). ¹H NMR (CDCl₃, 400 MHz) δ 7.45(s, 1H), 7.33 (s, 1H), 7.08 (d, J=8.4 Hz, 1H), 7.00 (s, 1H), 6.85-6.77(m, 2H), 4.04 (q, J=6.8 Hz, 2H), 3.92 (s, 3H), 2.65-2.61 (m, 2H),2.57-2.52 (m, 2H), 3.13 (s, 3H), 1.82-1.70 (m, 4H), 1.42 (t, J=6.8 Hz,3H). MS (ESI) m/z [M+H]⁺ 364.1

Compound 36 was prepared following the similar procedure for obtainingCompound 29 using (4-ethoxy-2-methylphenyl)boronic acid in place ofphenyl boronic acid (VIII-4) and tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylatein place of methyl boronic acid (VIII-6). ¹H NMR (CDCl₃, 400 MHz) δ 7.72(s, 2H), 7.19 (s, 1H), 7.10 (d, J=8.4 Hz, 1H), 6.92 (s, 1H), 6.85-6.82(m, 2H), 4.05 (q, J=6.8 Hz, 2H), 2.65-2.61 (m, 2H), 2.57-2.52 (m, 2H),2.01 (s, 3H), 1.80-1.70 (m, 4H), 1.35 (t, J=6.8 Hz, 3H). MS (ESI) m/z[M+H]⁺ 350.1.

Compound 37 was prepared following the similar procedure for obtainingCompound 29 using (4-(trifluoromethoxy)phenyl)boronic acid in place ofphenyl boronic acid (VIII-4) and tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylatein place of methyl boronic acid (VIII-6) as white solid. Na₂CO₃ wasreplaced with K₃PO₄. ¹H NMR (CDCl₃, 400 MHz) δ 7.60-7.52 (m, 2H), 7.46(d, J=8.4 Hz, 2H), 7.31 (d, J=8.4 Hz, 2H), 7.14 (s, 1H), 2.65-2.62 (m,2H), 2.52-2.49 (m, 2H), 1.82-1.70 (m, 4H). MS (ESI) m/z [M+H]⁺ 376.0.

Example 5-B Synthesis of Compound 38 (Scheme IX)

A mixture of IX-1 (14.2 g, 84.6 mmol), IX-2 (10.0 g, 76.9 mmol), NH₄OAc(12.0 g 153.8 mmol) in HOAc (18.6 g, 307.6 mmol) was heated at refluxfor 90 min. The mixture was allowed to cool to rt. Water (30 mL) wasadded and the reaction mixture was extracted with DCM (100 mL×3). Thecombined organic layer was washed with brine, dried over anhydrousNa₂SO₄ and concentrated in vacuo. The crude product was purified bycolumn chromatography with petroleum ether/EtOAc (5:1→1:1) to affordIX-3 (12 g, 67% yield) as yellow solid. MS (ESI) m/z [M+H]⁺ 234.1.

A mixture of IX-3 (12 g, 52 mmol) and DMF-dimethylacetal (6.2 g, 52mmol) in DMF (30 mL) was heated to reflux overnight. And then it wasallowed to cool to rt. The solvent was removed under reduced pressureand the residue was treated with 18% ammonia in methanol (50 mL) at 80°C. for 2 hrs. The solvent was removed under reduced pressure and theresulting residue was purified by column chromatography with petroleumether/EtOAc (2:1→1:2) yield IX-4 (2.3 g, 21% yield) as a yellow solid.MS (ESI) m/z [M+H]⁺ 214.9.

A solution of Br₂ (747 mg, 4.67 mmol) in HOAc (5 mL) was added dropwiseto a stirred solution of IX-4 (1 g, 4.67 mmol) in HOAc (10 mL). Uponcomplete addition, the reaction mixture was allowed to stir at rt for 30min before being heated at reflux for 2 hrs. Once the reaction mixturewas cooled to rt, water (20 mL) was added, the resultant precipitate wasfiltered off and air-dried. The product was then taken up in EtOAc (100mL), the organic layer was washed with water, saturated aqueous sodiumhydrogen carbonate, brine, dried over anhydrous Na₂SO₄, and concentratedin vacuo. The crude product was purified by column chromatography withpetroleum ether/EtOAc (2:1→1:2) to afford IX-5 (1.3 g, 95% yield) assolid. MS (ESI) m/z [M+H]⁺ 293.

To a stirred solution of IX-5 (500 mg, 1.7 mmol), IX-6 (380 mg, 1.88mmol), Cu(OAc)₂ (923 mg, 5.1 mmol) and pyridine (408 mg, 5.1 mmol) inDCM (10 mL) was added pyridine-N-oxide (484 mg, 5.1 mmol) in oneportion. The solution was refluxed under oxygen atmosphere overnight.After completion of the reaction indicated by TLC, the reaction mixturewas concentrated in vacuo. Dissolved the residue in ethyl acetate (100mL), filtered, and washed the filtrate with brine. The organic phase wasdried over anhydrous sodium sulfate, filtered, concentrated in vacuo toafford a yellowish solid. The crude product was purified by flash columnchromatography with petroleum ether/EtOAc (5:1→1:1) to afford IX-7 (600mg, 78% yield) as a yellow solid. MS (ESI) m/z [M+H]⁺ 453.

To a stirred mixture of IX-7 (250 mg, 0.55 mmol), IX-8 (116 mg, 0.83mmol), and Na₂CO₃ (117 mg, 1.1 mmol) in DME/H₂O (5 mL, v:v=5:1) wasadded Pd(dppf)Cl₂ (41 mg, 0.055 mmol). The mixture was purged withnitrogen for three times and then heated at 100° C. overnight. Themixture was concentrated to remove diluted with water (30 mL), extractedwith EtOAc (30 mL×3). The combined organic layer was washed with brine,dried over anhydrous Na₂SO₄ and concentrated in vacuo. The crude productwas purified by flash column chromatography with PE/EA (5:1→1:1) to giveCompound 38 (176.5 mg, 68% yield) as a yellow solid. ¹H NMR (DMSO-d₆,400 MHz) δ 8.94 (d, J=8.0 Hz, 1H), 8.08 (d, J=8.0 Hz, 1H), 7.99 (s, 1H),7.78-7.72 (m, 4H), 7.59-7.55 (m, 2H), 7.31-7.27 (m, 2H). MS (ESI) m/z[M+H]⁺ 469.1.

Compound 39 was prepared following the similar procedure for obtainingCompound 38 using1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole inreplace of IX-8. ¹H NMR (DMSO-d₆, 400 MHz) δ 8.91 (d, J=8.4 Hz, 1H),8.33 (s, 1H), 8.19 (s, 1H), 8.09-8.06 (m, 2H), 7.74-7.70 (m, 2H),7.60-7.57 (m, 2H), 3.87 (s, 3H). MS (ESI) m/z [M+H]⁺ 455.0.

Example 5-C Synthesis of Compound 40 (Scheme X)

To the mixture of X-1 (10.0 g, 10 mmol) dissolved in HBr 48% (200 mL),Br₂ (12.5 mL, 13.4 mmol) was added dropwise under ice-water coolingbath, maintaining the temperature below 40° C. After that, the mixturewas heated at 110° C. for 5 hrs. The reaction mixture was cooled to rt,filtered and washed with little water. The filter cake is basified to pH7-8 with saturated aq. NaHCO₃ and extracted with EtOAc (200 mL×3). Thecombined organic layer was washed with brine, dried over anhydrousNa₂SO₄ and concentrated to yield X-2 (17.2 g, 71% yield). ¹H NMR(DMSO-d₆, 400 MHz) δ 7.95 (s, 1H), 5.20 (brs, 4H).

X-2 (5.0 g, 18.9 mmol) was dissolved in SOCl₂ (50 mL). The mixture wasstirred at 100° C. for 5 hrs. Removed the excessive solvent, the residuewas diluted with EtOAc (200 mL), washed with brine, dried over Na₂SO₄.Filtration, concentration and the residue was X-3 (4.64 g, 100% yield).Compound 3 was used in next step without further purification. ¹H NMR(DMSO-d₆, 400 MHz) δ 8.55 (s, 1H).

X-3 (1.0 g, 4 mmol) was dissolved in water (10 mL), and then two dropsH₂O₂ (30%) and 2 drops conc. HCl was added. The mixture was stirred at100° C. for 15 min under microwave. After being cooled to rt, thereaction mixture was extracted with EtOAc (50 mL×3). The combinedorganic layer was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated in vacuo to afford X-4 (700 mg, 75% yield). X-4 was used innext step without further purification. ¹H NMR (DMSO-d₆, 400 MHz) δ11.97 (s, 1H), 7.81 (s, 1H).

To a solution of X-4 (330 mg, 1.4 mmol) in DCM (30 mL), Cu(OAc)₂ (800mg, 4.4 mmol), X-5 (500 mg, 2 mmol), pyridine (1 mL), pyridine-N-oxide(400 mg, 4 mmol) and finely ground, activated 4 Å molecular sieves (300mg) were added. The mixture was stirred at rt for 12 hrs under O₂atmosphere. The mixture was diluted with EtOAc (100 mL) and filtered,the filtrate was washed with brine, dried over Na₂SO₄, and concentrated.The residue was purified by flash column chromatography (PE/EtOAc=5/1)to give X-6 (280 mg, 50% yield) as a yellow solid. ¹H NMR (CDCl₃, 400MHz) δ 7.67 (s, 1H), 7.50-7.48 (m, 2H), 7.41-7.39 (m, 2H).

X-6 (230 mg, 0.58 mmol), X-7 (100 mg, 0.71 mmol) and K₂CO₃ (300 mg, 2.17mmol) were charged into 22 mL of DME/H₂O (v/v=10/1). The reactionmixture was degassed by N₂ for three times and then Pd(PPh₃)₄ (60 mg,0.052 mmol) was added. The reaction mixture was refluxed for 3 hrs.After being cooled to rt, the mixture was diluted with EtOAc (60 mL) andfiltered. The filtrate was washed with brine, dried over Na₂SO₄,concentrated. The residue was purified by flash column chromatography(PE/EtOAc=5/1) to give Compound 40 (150 mg, 63% yield) as a yellowsolid. ¹H NMR (CDCl₃, 400 MHz) δ 7.77-7.73 (m, 2H), 7.56-7.51 (m, 3H),7.41 (d, J=8.0 Hz, 2H), 7.22-7.17 (m, 2H). MS (ESI) m/z (M+H)⁺ 407.8.

Compound 41 was prepared following the similar procedure for obtainingCompound 40 using1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole inreplace of X-7. ¹H NMR (CDCl₃, 400 MHz) δ 8.23 (s, 1H), 7.85 (s, 1H),7.58 (s, 1H), 7.53 (d, J=8.8 Hz, 2H), 7.41 (d, J=8.8 Hz, 2H), 4.00 (s,3H). MS (ESI) m/z (M+H)⁺ 393.8.

Example 5-D Synthesis of Compound 42 (Scheme XI)

To the solution of XI-1 (10 g, 73 mmol, 1 eq) in 50 mL of DCM was added15 mL of oxalyl chloride (adding a drop of DMF). The mixture was stirredfor 18 hrs at rt. All the volatiles were removed under reduced pressure.The residue was dried and used directly for the next step (11.3 g, 100%yield). The solid was dissolved in 30 mL of DCM and added into 200 mL ofCH₂Cl₂—NH₃ at −30° C. The mixture was stirred for 18 hrs. LCMS analysisshowed the reaction completed. All the volatiles were removed underreduced pressure to afford XI-2 (7 g, 71% yield), which was useddirectly for the next step. ¹H NMR (DMSO-d₆, 400 MHz): δ 8.45 (m, 1H),7.93 (s, 1H), 7.71 (d, J=7.6 Hz, 1H), 7.54 (s, 1H), 7.23 (m, 1H), 2.48(s, 3H).

A mixture of XI-2 (13 g, 95.6 mmol, 1 eq) and 18.2 mL ofN,N-dimethylformamide dimethyl acetal was heated at 50° C. for 2 hrs.During the second hour, all the volatiles was removed. The residue wascooled to rt., diluted with 100 mL of anhydrous N,N-dimethylformamide,and then treated carefully with batch wise portions of sodium hydride (5g, 124.3 mmol, 1.3 eq, 60% oil dispersion; caution: vigorous evolutionof hydrogen). The mixture was heated at 80° C. for 2.5 hrs, and thenice-cooled, treated cautiously with 25 mL of 2-propanol, and thenmaintained at 0-5° C. overnight. The solid were collected, and thendissolved in 10 mL of hot water. The solution was filtered, the filtratewas ice-cooled and then treated dropwise with concentrated hydrochloricacid to pH=˜7.0. After storage at 0-5° C. for 3 hrs, the precipitatedsolids were collected, washed with ice-cold water, and dried in vacuumto give XI-3 (3 g, 32% yield). ¹H NMR (DMSO-d₆, 300 MHz): δ 8.90 (s,1H), 8.49 (d, J=7.6 Hz, 1H), 7.51-7.43 (m, 2H), 6.61 (d, J=7.6 Hz, 1H).

A suspension of XI-3 (2.36 g, 15.7 mmol, 1 eq), N-bromosuccinimide (3.1g, 17.3 mmol, 1 eq), and 50 mL of 1,2-dichloroethane was stirred at rtfor 3.5 hrs. The mixture was filtered; the solids were washedsuccessively with small amounts of chloroform, water, and diethyl ether,and then dried to leave XI-4 (0.8 g, 23% yield). MS (ESI) m/z (M+H)⁺226.8.

A flask was charged with XI-4 (0.6 g, 2.67 mmol, 1 eq.), XI-5 (1.1 g,5.33 mmol, 2 eq.), Cu(OAc)₂ (1.45 g, 8 mmol, 3 eq.), pyridine (2.1 g,26.7 mmol, 10 eq.), pyridine-N-oxide (0.76 g mg, 8.01 mmol, 3 eq.), 200mg of 4 Å molecular sieves and 45 mL of CH₂Cl₂. The mixture was stirredunder oxygen atmosphere at rt for 18 hrs. LCMS analysis showed thereaction completed. All the volatiles were removed under reducedpressure. The residue was diluted with water, extracted with ethylacetate (100 mL×3). The combined organic layer was washed with brine,dried over anhydrous sodium sulfate, filtered and concentrated to give abrown oil. Purification by column chromatography on silica gel withpetroleum ether/EtOAc (3:1→1:1) to provide XI-6 (0.5 g, 50% yield). MS(ESI) m/z (M+H)⁺ 386.8.

A flak was charged with XI-6 (140 mg, 0.36 mmol, 1 eq), XI-7 (76 mg,0.54 mmol, 1.5 eq), K₂CO₃ (100 mg, 0.72 mmol, 2 eq), Pd(dppf)Cl₂ (13 mg,0.018 mmol, 0.05 eq), 10 mL of DME and 2 mL of H₂O, and then it wasflushed with nitrogen for three times. The mixture was heated at 100° C.for 18 hrs. LCMS analysis showed the reaction completed. All thevolatiles were removed under reduced pressure. The residue was dilutedwith water, extracted with ethyl acetate (50 mL×3). The combined organiclayer was washed with brine, dried over anhydrous sodium sulfate,filtered and concentrated to give brown oil. Purification by prep-TLC(PE/EA=2/1) gave Compound 42 (102.4 mg, 71% yield). ¹H NMR (CDCl₃, 300MHz): δ 8.93 (m, 1H), 8.74 (d, J=7.8 Hz, 2H), 7.54-7.42 (m, 5H),7.39-7.31 (m, 3H), 7.09 (t, J=9.0 Hz, 2H). MS (ESI) m/z (M+H)⁺ 400.9.

Compound 43 was prepared following the similar procedure for obtainingCompound 42 using1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole inreplace of XI-7. ¹H NMR (CDCl₃, 400 MHz): δ 9.04 (m, 1H), 8.80 (d, J=8.4Hz, 1H), 8.22 (s, 1H), 7.80 (s, 1H), 7.58 (s, 1H), 7.56-7.51 (m, 3H),7.40 (d, J=8.4 Hz, 2H), 4.00 (s, 3H). MS (ESI) m/z (M+H)⁺ 386.9.

Compound 45: A flask was charged with Compound 42 (500 mg, 1.25 mmol, 1eq) and Pd/C (50 mg), 30 mL of MeOH and 3 mL of H₂O. The mixture wasstirred for 18 hrs under hydrogen (45 Psi). LCMS analysis showed thereaction completed. The mixture was filtered. The filtrate wasconcentrated and purified by prep-TLC (PE/EA=2/1) to give Compound 45 asa white solid (300 mg, 59% yield). ¹H NMR (CDCl₃, 400 MHz): δ 7.45 (d,J=8.8 Hz, 2H), 7.36-7.26 (m, 4H), 7.14 (t, J=8.8 Hz, 2H), 6.99 (s, 1H),4.30 (s, 1H), 3.29 (m, 2H), 2.67 (t, J=6.4 Hz, 2H), 1.93 (m, 2H). MS(ESI) m/z (M+H)⁺ 404.9.

Compound 44 was prepared following the similar procedure for obtainingCompound 45. ¹H NMR (CDCl₃, 300 MHz): δ 7.41 (s, 1H), 7.36-7.32 (m, 3H),7.20-7.15 (m, 2H), 6.90 (s, 1H), 4.41 (brs, 1H), 3.85 (s, 3H), 3.20 (m,2H), 2.54 (m, 2H), 1.82 (m, 2H). MS (ESI) m/z (M+H)⁺ 390.9.

Compound 395 was prepared following the similar procedure for obtainingCompound 43 using (4-cyanophenyl)boronic acid in place of XI-5. ¹H NMR(CDCl₃, 400 MHz) δ 9.10 (dd, J=1.6 Hz, 4.4 Hz, 1H), 8.79 (dd, J=2.0, 8.0Hz, 1H), 8.21 (s, 1H), 7.85 (d, J=8.4 Hz, 2H), 7.79 (s, 1H), 7.65 (d,J=8.4 Hz, 2H), 7.56-7.52 (m, 2H), 3.99 (s, 3H). MS (ESI) m/z(M+H)⁺328.0.

XI-6*with various R¹ groups can be prepared following the similarprocedure described in the synthesis of XI-6. The last Suzuki-Couplingstep was conducted either using Method 1 or Method 2 as describedherein. Compounds 571, 572 and 579-581 were prepared by Suzuki-Couplingof XI-6* with the corresponding XI-8* using standard procedure describedMethod A using K₃PO₄ in place of K₂CO₃. The HCl salts were prepared byreacting the compounds with aq. HCl (1.0M, 1.1 eq) at 0° C. in dioxnefor 20 mins then concentrated and dried in vacuo.

Compound 571: ¹H NMR (CDCl₃, 400 MHz) δ 9.03 (dd, J=2.0, 5.2 Hz, 1H),8.79 (dd, J=1.6, 8.0 Hz, 1H), 8.20 (s, 1H), 7.79 (s, 1H), 7.56 (s, 1H),7.53-7.50 (m, 3H), 7.43 (d, J=6.8 Hz, 2H), 3.99 (s, 3H). MS (ESI) m/z(M+H)⁺ 385.0.

Compound 572: ¹H NMR (DMSO-d₆, 400 MHz) δ 12.90 (s, 1H), 9.09 (dd,J=2.0, 4.8 Hz, 1H), 8.65 (dd, J=1.6, 8.0 Hz, 1H), 8.43 (s, 1H), 8.11 (s,1H), 8.01 (s, 1H), 7.66-7.63 (m, 5H). MS (ESI) m/z (M+H)⁺ 322.9.

Compound 579: ¹H NMR (DMSO-d₆, 400 MHz) δ 12.88 (s, 1H), 9.09 (dd,J=1.6, 4.4 Hz, 1H), 8.64 (dd, J=1.6, 8.0 Hz, 1H), 8.44 (s, 1H), 8.13 (s,1H), 8.05 (s, 1H), 7.73 (d, J=8.8 Hz, 2H), 7.66-7.62 (m, 1H), 7.58 (d,J=8.4 Hz, 2H). MS (ESI) m/z (M+H)⁺ 373.1.

Compound 580: ¹H NMR (DMSO-d₆, 300 MHz) δ 12.86 (s, 1H), 9.09 (dd,J=1.8, 4.5 Hz, 1H), 8.65 (dd, J=1.8, 8.1 Hz, 1H), 8.43 (s, 1H), 8.10 (s,1H), 7.86 (s, 1H), 7.65-7.62 (m, 1H), 7.30-7.23 (m, 1H), 6.99 (d, J=2.4Hz, 1H), 6.93-6.89 (m, 1H), 4.09 (q, J=7.2 Hz, 2H), 2.07 (s, 3H), 1.37(t, J=7.2 Hz, 3H). MS (ESI) m/z (M+H)⁺ 347.1.

Compound 581: ¹H NMR (DMSO-d₆, 300 MHz) δ 12.90 (s, 1H), 9.09 (d, J=3.0Hz, 1H), 8.66 (d, J=7.2 Hz, 1H), 8.34 (s, 1H), 8.08-8.04 (m, 4H), 7.85(d, J=8.1 Hz, 2H), 7.67-7.64 (m, 2H). MS (ESI) m/z (M+H)⁺ 314.1.

Example 5-E Synthesis of Compound 46 (Scheme XII)

To the mixture of XII-1 (10.0 g, 10 mmol) dissolved in HBr 48% (200 mL),Br₂ (12.5 mL, 13.4 mmol) was added dropwise under ice-water coolingbath, maintaining the temperature below 40° C. After that, the mixturewas heated at 110° C. for 5 hrs. The reaction mixture was cooled to rt,filtered and washed with little water. The filter cake is basified to pH7-8 with saturated aq. NaHCO₃ and extracted with EtOAc (200 mL×3). Thecombined organic layer was washed with brine, dried over anhydrousNa₂SO₄ and concentrated to yield XII-2 (17.2 g, 71% yield). ¹H NMR(DMSO-d₆, 400 MHz) δ 7.95 (s, 1H), 5.20 (brs, 4H).

XII-2 (5.0 g, 18.9 mmol) and aqueous glyoxal (40%, 5 mL) was dissolvedin n-BuOH (15 mL), the mixture was stirred at 80° C. for 2 hrs. Thereaction mixture was cooled to rt, a solid was precipitated out,filtered, washed with PE and dried in vacuum to afford XII-3 (5.0 g, 92%yield) as a yellow solid, which was used in next step without furtherpurification. ¹H NMR (CDCl₃, 400 MHz) δ 9.18 (d, J=2.0 Hz, 1H), 9.11 (d,J=2.0 Hz, 1H), 8.84 (s, 1H).

XII-3 (5.0 g, 17.3 mmol) and NaOMe (1.4 g, 26 mmol) were dissolved inMeOH (60 mL), and then the mixture was stirred at 60° C. for 0.5 h.Removed the solvent, diluted with EtOAc (100 mL), washed with brine,dried over Na₂SO₄ and concentrated to give XII-4 (3.7 g, 89% yield) as alight yellow solid, which was used in next step without furtherpurification. ¹H NMR (CDCl₃, 300 MHz) δ 9.05 (d, J=1.8 Hz, 1H), 8.88 (d,J=1.8 Hz, 1H), 8.46 (s, 1H), 4.17 (s, 3H).

XII-4 (2.0 g, 8.4 mmol) and NaSEt (3.2 g, 38 mmol) was dissolved in DMF(30 mL), the mixture was stirred at 60° C. for 1.5 hrs. The reactionmixture was cooled to rt, diluted with water (30 mL) and acidified topH=6-7 with conc. HCl. The precipitate was collected by filtration,washed with water and dried in vacuum to afford XII-5 (1.9 g, 100%yield) as a brown solid. ¹H NMR (DMSO-d₆, 400 MHz) δ 8.84 (d, J=2.0 Hz,1H), 8.57 (d, J=1.6 Hz, 1H), 7.95 (s, 1H).

To a solution of XII-5 (2.0 g, 10 mmol) in DCM (100 mL), copper (II)acetate (3.6 g, 20 mmol), XII-6 (2.0 g, 12 mmol), pyridine (3 mL),pyridine-N-oxide (1.9 g, 20 mmol) and finely ground, activated 4 Åmolecular sieves (3.0 g) were added. The mixture was stirred at rt. for18 hrs under O₂ atmosphere. The solvent was evaporated and the residuewas diluted with AcOEt (150 mL) and filtered. The filtrate was washedwith brine, dried over Na₂SO₄ and concentrated. The residue was purifiedby flash chromatography on silica gel with petroleum ether/EtOAc(1:1˜1:2) to yield XII-7 (400 mg, 12% yield) as a yellow solid. MS (ESI)m/z (M+H)⁺ 386.

Compound 46 was prepared following the similar procedure for obtainingCompound 42 (75 mg, 72% yield). ¹H NMR (CD₃OD, 400 MHz) δ 9.01 (d, J=2.0Hz, 1H), 8.89 (d, J=2.0 Hz, 1H), 7.83 (s, 1H), 7.73-7.70 (m, 2H),7.68-7.65 (m, 2H), 7.51 (d, J=8.0 Hz, 2H), 7.21-7.16 (m, 2H). MS (ESI)m/z (M+H)⁺ 401.9.

Compound 47 was prepared following the similar procedure for obtainingCompound 46 using1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole inreplace of XII-8. ¹H NMR (CD₃OD, 400 MHz) δ 9.01 (d, J=2.0 Hz, 1H), 8.89(d, J=2.0 Hz, 1H), 8.35 (s, 1H), 8.04 (m, 2H), 7.73-7.70 (m, 2H),7.55-7.50 (m, 2H), 3.97 (s, 3H). MS (ESI) m/z (M+H)⁺ 387.9.

Compound 397 was prepared following the similar procedure for obtainingCompound 47 using XII-6a in place of XII-6. ¹H NMR (CDCl₃, 400 MHz) δ8.98 (d, J=2.0 Hz, 1H), 8.90 (d, J=2.0 Hz, 1H), 8.13 (s, 1H), 7.80 (s,1H), 7.64 (s, 1H), 7.55-7.52 (m, 2H), 7.47-7.45 (m, 2H), 4.00 (s, 3H).MS (ESI) m/z [M+H]⁺ 337.9.

Compound 398 was prepared following the similar procedure for obtainingCompound 397 using (4-cyanophenyl)boronic acid in place of XII-6a. ¹HNMR (CDCl₃, 400 MHz) δ 9.00 (d, J=2.0 Hz, 1H), 8.93 (d, J=2.0 Hz, 1H),8.14 (s, 1H), 7.89-7.87 (m, 2H), 7.81 (s, 1H), 7.71-7.67 (m, 2H), 7.64(s, 1H), 4.00 (s, 3H). MS (ESI) m/z [M+H]⁺ 328.9.

To a solution of XII-7a (400 mg, 1.2 mmol, 1 eq.) in DMF (4 mL) wasadded aq. K₃PO₄ (2 M, 1.2 mL, 2.4 mmol, 2 eq.), XII-8b (425 mg, 1.44mmol, 1.2 eq.), Pd(PPh₃)₄ (67 mg, 0.06 mmol, 0.05 eq.). The mixture waspurged with nitrogen and then heated at 80° C. for 5 hrs. The mixturewas cooled to rt, diluted with water (20 mL), extracted with EtOAc (30mL×3). The combined organic layer was washed with brine, dried overanhydrous Na₂SO₄, and concentrated in vacuo. The residue was purified byflash chromatography (PE/EA=1/3) to give Compound 399 (90 mg, 24%yield). ¹H NMR (CDCl₃, 400 MHz) δ 8.99 (d, J=2.0 Hz, 1H), 8.93 (d, J=2.0Hz, 1H), 8.15 (s, 2H), 7.68 (s, 1H), 7.56-7.52 (m, 2H), 7.48-7.46 (m,2H). MS (ESI) m/z [M+H]⁺ 323.9.

To the mixture of Compound 399 (85 mg, 0.365 mmol) in MeOH (5 mL) andCH₃CN (5 mL) was added aq.HCl (0.2 M, 2 mL, 0.4 mmol, 1.1 eq.). Afterstirring for 0.5 h, removed the solvent under reduced pressure, and theresidue was dried in vacuum to afford the hydrochloride salt Compound399a as a yellow solid (120 mg, 91% yield). ¹H NMR (DMSO-d₆, 400 MHz) δ9.12 (d, J=2.0 Hz, 1H), 8.95 (d, J=2.0 Hz, 1H), 8.28 (s, 2H), 8.11 (s,1H), 7.68-7.62 (m, 4H). MS (ESI) m/z [M+H]⁺ 323.9.

Compound 400 was prepared following the similar procedure for obtainingCompound 399 by reacting XII-7 with XII-8b. ¹H NMR (CD₃OD, 400 MHz) δ9.09 (d, J=1.6 Hz, 1H), 8.88 (d, J=1.6 Hz, 1H), 8.35-8.20 (m, 2H), 8.05(s, 1H), 7.71-7.68 (m, 2H), 7.52-7.50 (m, 2H). MS (ESI) m/z [M+H]⁺374.2.

The hydrochloride salt of Compound 400 was prepared following thesimilar procedure for obtaining Compound 399a as a yellow solid. ¹H NMR(DMSO-d₆, 400 MHz) δ 9.12 (d, J=2.0 Hz, 1H), 8.95 (d, J=2.0 Hz, 1H),8.29 (s, 2H), 8.16 (s, 1H), 7.76-7.73 (m, 2H), 7.62-7.59 (m, 2H). MS(ESI) m/z [M+H]⁺ 374.0.

Compounds 573 and 574 were prepared by following the similar proceduredescribed in the synthesis of Compound 399. The corresponding HCl saltswere also prepared following the similar procedure described in thesynthesis of Compound 399a.

Compounds 573: ¹H NMR (DMSO-d₆, 400 MHz) δ 12.93 (s, 1H), 9.11 (d, J=1.6Hz, 1H), 8.93 (d, J=1.6 Hz, 1H), 8.37 (s, 1H), 8.12-8.06 (m, 4H),7.84-7.82 (m, 2H). MS (ESI) m/z (M+H)⁺ 315.0.

Compound 574: ¹H NMR (DMSO-d₆, 400 MHz) δ 12.93 (s, 1H), 9.12 (s, 1H),8.94 (s, 1H), 8.40 (s, 1H), 8.11 (s, 1H), 7.98 (s, 1H), 7.32 (m, 1H),7.00 (m, 1H), 6.91 (m, 1H), 4.10 (q, J=6.8 Hz, 2H), 2.09 (s, 3H), 1.37(t, J=6.8 Hz, 3H). MS (ESI) m/z (M+H)⁺ 348.1.

Compound 575: To a solution of XII-7 (300 mg, 0.78 mmol) in DMF (5 mL)was added Pd(OAc)₂ (9 mg, 0.039 mmol), Et₃N (240 mg, 2.4 mmol), HCOOH(72 mg, 1.5 mmol) and PPh₃ (20.4 mg, 0.078 mmol). The mixture was purgedwith nitrogen for three times and then heated at 60° C. under nitrogenfor 12 hrs. After cooling to rt, the mixture was concentrated, theresidue was partitioned between H₂O and EtOAc. The organic layer waswashed with brine, dried over Na₂SO₄, concentrated in vacuo. The cruderesidue was purified by column chromatography on silica gel using EA aseluent to afford Compound 575 (146 mg, 61% yield). ¹H NMR (DMSO-d₆, 300MHz) δ 9.02 (d, J=1.5 Hz, 1H), 8.88 (d, J=1.8 Hz, 1H), 7.89 (d, J=7.5Hz, 1H), 7.70 (d, J=8.7 Hz, 2H), 7.60 (d, J=8.4 Hz, 2H), 6.82 (d, J=7.5Hz, 1H).

Compound 577 was prepared by Suzuki-coupling of XII-7 with XII-8b inDMF/H₂O at 100° C. for 12 h followed by reacting with 1,3-dioxolan-2-onein the presence of NaOH. ¹H NMR (DMSO-d₆, 300 MHz) δ 9.12 (s, 1H), 8.95(s, 1H), 8.42 (s, 1H), 8.15 (s, 1H), 8.07 (s, 1H), 7.75 (d, J=8.7 Hz,2H), 7.61 (d, J=8.7 Hz, 2H), 4.18 (d, J=5.7 Hz, 2H), 3.77 (d, J=6.9 Hz,2H).

Compound 576 was prepared by Suzuki-Coupling of XII-4 and XII-8b usingthe standard procedure described herein followed by reaction with BBr₃in DCM. ¹H NMR (DMSO-d₆, 300 MHz) δ 12.83 (s, 1H), 9.04 (s, 1H), 8.84(s, 1H), 8.17 (s, 1H), 7.82 (s, 1H).

Compound 578 was prepared following the similar procedure described inthe synthesis of Compound 576 using1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole inplace of XII-8b. ¹H NMR (DMSO-d₆, 300 MHz) δ 8.99 (s, 1H), 8.80 (s, 1H),8.27 (s, 1H), 7.93 (s, 1H), 7.84 (s, 1H), 3.88 (s, 3H).

Example 5-F Synthesis of Compound 48 (Scheme XIII)

A suspension of XIII-1 (10.3 g, 73.4 mmol, 1 eq) in 46 mL of aceticacid, 20 mL of water, 1.4 mL of concentrated sulfuric acid and periodicacid (3.5 g, 18 mmol, 0.25 eq) was stirred at 90° C. for 15 minuteswhereby a solution was obtained. Iodine crystals (7.7 g, 30.1 mmol, 0.4eq) were added portionwise and after 20 minutes a dense yellowprecipitate had formed. The mixture was cooled and saturated sodiumthiosulphate (50 mL) was added. The solid was filtered and washed withsaturated sodium thiosulphate (50 mL) followed by water. The solid wasdried under vacuum to afford XIII-2 (14 g, 72% yield).

A suspension of XIII-2 (15 g, 56.4 mmol, 1 eq.) in 35 mL of phenyldichlorophosphate was heated at 180° C. for 30 minutes whereby a brownsolution was obtained. TLC analysis (PE:EA=10:1) showed the reactioncompleted. The solution was allowed to cool then poured onto ice/water,neutralized by a portionwise addition of solid NaHCO₃ and extracted withethyl acetate (150 mL×3), and then washed with aq. NaHCO₃ (5%, 50 mL).The organic layer was dried over anhydrous sodium sulfate, filtered andconcentrated to give brown solid. The crude product was purified byflash chromatography on silica gel with petroleum ether/EtOAc (5:1→2:1)to give XIII-3 as yellow solid (14 g, 87% yield). MS (ESI) m/z (M+H)⁺284.7.

To a solution of vinyl magnesium bromide (66 mL, 66 mmol, 3.4 eq, 1.0 Msolution in 2-methyl tetrahydrofuran) at −70° C. under nitrogen wasadded a solution of XIII-3 (5.5 g, 19.3 mmol, 1 eq.) in 120 mL of drytetrahydrofuran, dropwise over 45 min. After 30 min at −70° C. TLCanalysis (PE:EA=3:1) showed the starting material was consumedcompletely. The reaction was quenched with saturated ammonium chloride(50 mL). The mixture was extracted with ethyl acetate (150 mL×3). Thecombined organic layers was washed with brine, dried over anhydroussodium sulfate, filtered and concentrated to give a brown oil. It waspurified by flash chromatography on silica gel with petroleumether/EtOAc (5:1→2:1) to give XIII-4 (0.5 g, 9% yield). MS (ESI) m/z(M+H)⁺ 278.8.

A flask was charged with XIII-4 (450 mg, 1.6 mmol, 1 eq), NaOMe (864 mg,16 mmol, 10 eq.) and 8 mL of DMF. The mixture was heated at 130° C. for18 hrs. LCMS analysis showed the reaction completed. The reactionmixture was cooled down to rt, diluted with water, extracted with ethylacetated (50 mL×3). The combined organic layer was washed with brine,dried over anhydrous sodium sulfate, filtered and concentrated to yieldXIII-5 (0.2 g, 46% yield). MS (ESI) m/z (M+H)⁺ 274.8.

XIII-7 was prepared following the similar procedure for obtainingCompound 42 using1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(XIII-6) in replace of XI-7. (150 mg, 51% yield). MS (ESI) m/z (M+H)⁺228.9.

To a solution of XIII-7 (100 mg, 0.44 mmol, 1 eq.) in DMF (5 mL) wasadded NaH (60% in mineral oil, 35 mg, 0.88 mmol, 2 eq.). After stirringfor 30 min, MeI (75 mg, 0.53 mmol, 1.2 eq.) was added. The mixture wasstirred at rt. for 2 hrs. And then it was slowly quenched with water,extracted with EtOAc (30 mL×3). The combined organic layer was washedwith brine, dried over anhydrous Na₂SO₄ and concentrated. The residuewas purified by prep-TLC (PE/EA=1:2) to afford XIII-8 (90 mg, 85%yield). MS (ESI) m/z (M+H)⁺ 243.0.

A mixture of XIII-8 (90 mg, 0.374 mmol) in 10 mL aq.HBr (48%) was heatedto reflux overnight. After being cooled to rt, the mixture wasneutralized by addition of saturated aq. NaHCO₃, extracted withDCM/i-PrOH (30 mL×3, v/v=9/1). The combined organic layer was washedwith brine, dried over anhydrous Na₂SO₄ and concentrated to afford crudeXIII-9 (70 mg, 82% yield). MS (ESI) m/z (M+H)⁺ 229.0.

Compound 48 was prepared following the similar procedure for obtainingXII-7. (51.9 mg, 43% yield). ¹H NMR (CDCl₃, 300 MHz): δ 7.63 (s, 1H),7.53 (s, 1H), 7.42 (d, J=8.7 Hz, 2H), 7.27 (d, J=8.7 Hz, 2H), 7.03 (d,J=3.0 Hz, 1H), 6.95 (s, 1H), 6.39 (d, J=3 Hz, 1H), 4.10 (s, 3H), 3.90(s, 3H). MS (ESI) m/z (M+H)⁺ 388.9.

Compound 49 was prepared following the similar procedure for obtainingCompound 48 using 1-propenylmagnesium bromide in place of vinylmagnesium bromide and (4-fluorophenyl)boronic acid in place of XIII-6.¹H NMR (CDCl₃, 300 MHz) δ 7.43 (d, J=8.7 Hz, 2H), 7.32-7.29 (m, 4H),7.02 (t, J=8.4 Hz, 2H), 6.77 (s, 1H), 6.71 (s, 1H), 4.08 (s, 3H), 1.69(s, 3H). MS (ESI) m/z (M+H)⁺ 416.9.

XIII-7a was prepared following the similar procedure for obtainingCompound 42. MS (ESI) m/z (M+H)⁺ 246.9.

To a solution of XIII-7a (400 mg, 1.63 mmol, 1 eq.) in 10 mL of DMF wasadded NaH (60% dispersion in mineral oil, 98 mg, 2.44 mmol, 1.5 eq.) at0° C. The mixture was stirred at 0° C. for 30 min. After that, BnBr (417mg, 2.44 mmol, 1.5 eq.) was added into the flask. The resulting mixturewas stirred for 16 hrs at rt. TLC (PE/EA=5/1) analysis showed thereaction completed. The mixture was diluted with water, extracted withEtOA (50 mL×3). The combined organic layer was washed with brine, driedover Na₂SO₄, filtered and concentrated to give a yellow oil.Purification by column chromatography on silica gel (PE/EA=5/1) affordXIII-8a (250 mg, 46% yield). MS (ESI) m/z (M+H)⁺ 336.9.

A flask was charged with XIII-8a (250 mg, 0.74 mmol, 1 eq.), KOH (499mg, 8.9 mmol, 12 eq.), L₁ (97 mg, 0.23 mmol, 0.3 eq.), 10 mL of dioxaneand 10 mL of H₂O. The flask was flushed with nitrogen, and thenPd₂(dba)₃ (37 mg, 0.04 mmol, 0.05 eq.) was added. The mixture wasflushed with nitrogen again, and heated to reflux for 10 hrs. LCMSanalysis showed the reaction completed. The mixture was cooled down tort, diluted with water (20 mL), extracted with ethyl acetate (50 mL×3).The combined organic layer was washed with brine, dried over anhydroussodium sulfate, filtered and concentrated. Purification by prep-TLC(PE/EA=1/1) gave Compound 590 (200 mg, 85% yield). MS (ESI) m/z (M+H)⁺318.9.

Compound 392 was prepared by Suzuki Coupling of Compound 590 withXIII-10 following the similar procedure for obtaining Compound 48 (19%yield). ¹H NMR (CDCl₃, 400 MHz) δ 7.53-7.50 (m, 4H), 7.36-7.27 (m, 7H),7.19 (d, J=2.8 Hz, 1H), 7.14 (t, J=8.4 Hz, 2H), 7.01 (s, 1H), 6.46 (d,J=2.8 Hz, 1H), 5.86 (s, 2H). MS (ESI) m/z (M+H)⁺ 479.1.

To a solution of Compound 392 (220 mg, 0.51 mmol, 1 eq) and DMSO (400mg, 5.14 mmol, 10 eq) in 20 mL of THF was added KOt-Bu (1.15 g, 10.28mmol, 20 eq) at 0° C. The mixture was stirred for 18 h at rt underoxygen. The reaction was quenched with water, extracted with EtOAc. Thecombined organic layer was washed with brine, dried over anhydroussodium sulfate, filtrated and concentrated. Purification by prep-TLC(PE: EA=1:1) gave Compound 591 as a white solid (140 mg, 70% yield). ¹HNMR (DMSO-d₆, 400 MHz) δ 12.37 (s, 1H), 7.69-7.65 (m, 4H), 7.51 (d,J=8.4 Hz, 2H), 7.44 (t, J=2.8 Hz, 1H), 7.29-7.25 (m, 3H), 6.48 (t, J=2.4Hz, 1H). MS (ESI) m/z (M+H)⁺ 388.9.

To a solution of Compound 591 (200 mg, 0.52 mmol, 1 eq) in 5 mL of DMFwas added Cs₂CO₃ (336 mg, 1.03 mmol, 2 eq) at rt. The mixture wasstirred for 30 min. MeI (146 mg, 1.03 mmol, 2 eq) was added into theflask. The mixture was stirred for 18 h at rt. The mixture was dilutedwith water, extracted with EtOAc. The combined organic layer was washedwith brine, dried over Na₂SO₄, filtered and concentrated to give yellowsolid. Purification by prep-TLC (PE:EA=1:1) gave Compound 592 as a lightyellow solid (90 mg, 43% yield). ¹HNMR (DMSO-d₆, 400 MHz) δ 7.68-7.64(m, 4H), 7.52 (d, J=8.0 Hz, 2H), 7.48 (d, J=2.8 Hz, 1H), 7.31-7.26 (m,3H), 6.42 (d, J=2.8 Hz, 1H), 4.11 (s, 3H). MS (ESI) m/z (M+H)⁺ 403.1.

Compound 394 was prepared following the similar procedure for obtainingCompound 392 and using 4-bromo-7-chloro-1H-pyrrolo[2,3-c]pyridine inplace of XIII-4, XIII-6 in place of XIII-6a, and methyl iodide in placeof BnBr. ¹H NMR (CDCl₃, 400 MHz) δ 7.70 (s, 1H), 7.60 (s, 1H), 7.49 (d,J=8.4 Hz, 2H), 7.34 (d, J=8.4 Hz, 2H), 7.10 (d, J=2.8 Hz, 1H), 7.02 (s,1H), 6.46 (d, J=2.8 Hz, 1H), 4.20 (s, 3H), 3.97 (s, 3H). MS (ESI) m/z(M+H)⁺ 389.0.

Compound 593 was prepared following the similar procedure for obtainingCompound 48 using XIII-4b in place of XIII-4. The ethylation by EtI andtreatment with NaOMe were conducted following the similar proceduredescribed in the synthesis of Compound 592 and XIII-5. After HBrhydrolysis, XIII-7b was subject to two Suzuki-Coupling reactions toafford Compound 593 as a white solid. ¹H NMR (DMSO-d₆, 400 MHz) δ 12.94(s, 1H), 8.05-7.98 (m, 2H), 7.63-7.61 (m, 2H), 7.52-7.49 (m, 3H), 7.38(s, 1H), 6.61 (d, J=2.4 Hz, 1H), 4.51 (q, J=7.2 Hz, 2H), 1.33 (t, J=7.2Hz, 3H). MS (ESI) m/z (M+H)⁺ 389.1.

HCl salt compound 593a: ¹H NMR (DMSO-d₆, 400 MHz) δ 8.01 (s, 2H), 7.62(d, J=8.8 Hz, 2H), 7.98 (s, 1H), 7.53-7.50 (m, 3H), 7.38 (s, 1H), 6.61(d, J=8.8 Hz, 1H), 4.51 (q, J=7.2 Hz, 2H), 1.33 (t, J=7.2 Hz, 3H). MS(ESI) m/z [M+H]⁺ 389.1.

Compound 595 was obtained by Suzuki-Coupling of XIII-4b with XIII-6a,followed by dechlorination following the same procedure described abovein the dechlorination of XIII-8a. ¹H NMR (CDCl₃, 400 MHz) δ 11.18 (s,1H), 7.52-7.49 (m, 2H), 7.16-7.11 (m, 3H), 6.97 (s, 1H), 6.41 (d, J=3.2Hz, 1H), 4.66 (q, J=7.2 Hz, 2H), 1.52 (t, J=7.2 Hz, 3H). MS (ESI) m/z(M+H)⁺ 257.1.

Compound 594 was obtained by Suzuki Coupling of Compound 595 withXIII-10 following the same procedure for obtaining Compound 48. ¹H NMR(CDCl₃, 400 MHz) δ 7.54-7.51 (m, 2H), 7.35 (d, J=8.4 Hz, 1H), 7.18-7.12(m, 3H), 7.00 (s, 1H), 6.42 (d, J=2.4 Hz, 1H), 4.62 (q, J=7.2 Hz, 2H),1.51 (t, J=7.2 Hz, 3H). MS (ESI) m/z (M+H)⁺ 417.2.

Compound 615 was obtained as a white solid by reacting Compound 593 with2-(2-bromoethoxy)tetrahydro-2H-pyran in the presence of Cs₂CO₃ in DMF at50° C., followed by hydroxy deprotection using TsOH in MeOH at 60° C. ¹HNMR (DMSO-d₆, 400 MHz) δ 8.12 (s, 1H), 7.83 (s, 1H), 7.64 (d, J=8.8 Hz,2H), 7.55-7.51 (m, 3H), 7.38 (s, 1H), 4.92 (t, J=5.2 Hz, 1H), 4.57 (q,J=7.2 Hz, 2H), 4.16 (t, J=5.6 Hz, 2H), 3.76 (q, J=4.6 Hz, 2H), 1.35 (t,J=7.2 Hz, 3H). MS (ESI) m/z (M+H)⁺ 433.0.

Compound 596 was prepared by following the similar procedure for thepreparation of Compound 48. ¹H NMR (DMSO-d₆, 400 MHz) δ 8.13 (s, 1H),7.82 (s, 1H), 7.66-7.62 (m, 3H), 7.53-7.51 (m, 2H), 7.40 (s, 1H),7.31-7.25 (m, 5H), 6.68 (d, J=2.8 Hz, 1H), 5.77 (s, 2H), 3.87 (s, 3H).MS (ESI) m/z (M+H)⁺ 465.1.

HCl salt compound 596a: ¹H NMR (DMSO-d₆, 400 MHz) δ 8.11 (s, 1H), 7.80(s, 1H), 7.64-7.60 (m, 3H), 7.51-7.49 (m, 3H), 7.39 (s, 1H), 7.31-7.22(m, 5H), 6.66 (d, J=2.8 Hz, 1H), 5.76 (s, 2H), 3.85 (s, 3H). MS (ESI)m/z (M+H)⁺ 465.1.

Compound 614 was obtained by amino deprotection of Compound 596 usingKO^(t)Bu, followed by reaction with 2-(2-bromoethoxy)tetrahydro-2H-pyranin the presence of Cs₂CO₃ in DMF, then hydroxy deprotection using TsOHin MeOH. ¹H NMR (DMSO-d₆, 400 MHz) δ 8.12 (s, 1H), 7.82 (s, 1H), 7.63(d, J=6.8 Hz, 2H), 7.52 (d, J=8.4 Hz, 2H), 7.47 (s, 1H), 7.38 (s, 1H),6.60 (d, J=2.8 Hz, 1H), 4.54 (t, J=6.0 Hz, 2H), 3.87 (s, 3H), 3.70 (t,J=5.6 Hz, 2H). MS (ESI) m/z (M+H)⁺419.1.

Compound 597 was prepared by following the similar procedure for thepreparation of Compound 48 using (4-cyanophenyl)boronic acid in place ofXIII-10. ¹H NMR (DMSO-d₆, 400 MHz) δ 8.11 (s, 1H), 7.99 (d, J=8.5 Hz,2H), 7.80 (s, 1H), 7.72 (d, J=8.5 Hz, 2H), 7.46 (d, J=2.8 Hz, 1H), 7.35(s, 1H), 6.60 (d, J=2.8 Hz, 1H), 4.07 (s, 3H), 3.85 (s, 3H).

HCl salt compound 597a: ¹H NMR (DMSO-d₆, 400 MHz) δ 8.13 (s, 1H), 8.01(d, J=7.5 Hz, 2H), 7.78 (m, 3H), 7.48 (s, 1H), 7.37 (s, 1H), 6.62 (s,1H), 4.09 (s, 3H), 3.86 (s, 3H).

Compound 600 was prepared by following the similar procedure for thepreparation of Compound 597 using the Boc-protected boronic ester inplace of XIII-6. ¹H NMR (DMSO-d₆, 400 MHz) δ 12.95 (s, 1H), 8.13 (s,1H), 7.99 (d, J=8.4 Hz, 2H), 7.87 (s, 1H), 7.73 (d, J=8.4 Hz, 2H), 7.45(d, J=2.8 Hz, 1H), 7.37 (s, 1H), 6.61 (d, J=2.8 Hz, 1H), 4.08 (s, 3H).

HCl salt compound 600a: ¹H NMR (DMSO-d₆, 400 MHz) δ 8.00 (m, 4H), 7.74(d, J=8.0 Hz, 2H), 7.46 (m, 1H), 7.37 (s, 1H), 6.61 (d, J=2.4 Hz, 1H),4.08 (s, 3H).

Compound 599 was obtained by Suzuki-Coupling of4-bromo-1-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one with(4-chlorophenyl)boronic acid then Suzuki-Coupling with XIII-6, followingthe similar procedure described in the synthesis of XIII-8b and Compound593. ¹H NMR (DMSO-d₆, 400 MHz) δ 8.10 (s, 1H), 7.78 (s, 1H), 7.57 (m,2H), 7.50 (m, 2H), 7.44 (d, J=2.8 Hz, 1H), 7.30 (s, 1H), 6.58 (d, J=2.8Hz, 1H), 4.07 (s, 3H), 3.85 (s, 3H).

Compound 598 was prepared by following the similar procedure for thepreparation of Compound 599 using the Boc-protected boronic ester inplace of XIII-6. ¹H NMR (DMSO-d₆, 400 MHz) δ 12.95 (s, 1H), 8.13 (s,1H), 7.88 (s, 1H), 7.59 (m, 2H), 7.52 (m, 2H), 7.45 (d, J=2.8 Hz, 1H),7.34 (s, 1H), 6.62 (d, J=2.8 Hz, 1H), 4.10 (s, 3H).

HCl salt compound 598a: ¹H NMR (DMSO-d₆, 400 MHz) δ 8.05 (d, J=2 Hz,2H), 7.56 (m, 2H), 7.50 (m, 2H), 7.44 (d, J=2.8 Hz, 1H), 7.34 (s, 1H),6.6 (d, J=2.8 Hz, 1H), 4.07 (s, 3H).

Compounds 601 and 602 was prepared following the similar proceduredescribed in the synthesis of Compound 598 using the correspondingaromatic boronic acids. Their respective HCl salts compounds 601a and602a were also obtained by reacting with aq. HCl in acetonitrile.

Compound 601: ¹H NMR (DMSO-d₆, 400 MHz) δ 12.90 (s, 1H), 8.09 (s, 1H),7.84 (s, 1H), 7.40 (d, J=2.4 Hz, 1H), 7.14 (d, J=8.0 Hz, 2H), 6.92 (d,J=2.0 Hz, 1H), 6.85 (d, J=8.0 Hz, 1H), 6.59 (d, J=2.8 Hz, 1H), 4.07 (m,5H), 2.02 (s, 3H), 1.34 (t, J=6.8 Hz, 3H). MS (ESI) m/z (M+H)⁺ 349.0.

Compound 601a: ¹H NMR (DMSO-d₆, 400 MHz) δ 8.04 (s, 2H), 7.42 (d, J=2.8Hz, 1H), 7.15 (d, J=8.4 Hz, 2H), 6.93 (d, J=2.4 Hz, 1H), 6.85 (d, J=8.4Hz, 1H), 6.61 (d, J=2.8 Hz, 1H), 4.09-4.05 (m, 5H), 2.04 (s, 3H), 1.35(t, J=6.8 Hz, 3H). MS (ESI) m/z (M+H)⁺ 348.9.

Compound 602: ¹H NMR (DMSO-d₆, 400 MHz) δ 12.94 (s, 1H), 8.13 (s, 1H),7.89 (s, 1H), 7.62 (d, J=8.4 Hz, 2H), 7.51 (d, J=8.4 Hz, 2H), 7.45 (d,J=2.4 Hz, 1H), 7.38 (s, 1H), 6.62 (d, J=3.2 Hz, 1H), 4.09 (s, 3H).

Compound 602a: ¹H NMR (DMSO-d₆, 400 MHz) δ 8.06 (s, 2H), 7.62 (d, J=8.0Hz, 2H), 7.51 (d, J=8.0 Hz, 2H), 7.46 (d, J=2.8 Hz, 1H), 7.40 (s, 1H),6.62 (d, J=2.8 Hz, 1H), 4.09 (s, 3H). MS (ESI) m/z (M+H)⁺ 374.9.

Compound 603 was prepared by benzyl deprotection of1-benzyl-4-bromo-6-(4-(trifluoromethoxy)phenyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-oneto form an intermediate4-bromo-6-(4-(trifluoromethoxy)phenyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one,followed by Suzuki-Coupling with XIII-6 to afford the final product. ¹HNMR (DMSO-d₆, 400 MHz) δ 12.29 (s, 1H), 8.14 (s, 1H), 7.83 (s, 1H), 7.64(d, J=8.8 Hz, 2H), 7.52 (d, J=8.8 Hz, 2H), 7.43 (m, 1H), 7.38 (s, 1H),6.66 (m, 1H), 3.86 (s, 3H). MS (ESI) m/z (M+H)⁺ 375.0.

Compound 604 was prepared by Suzuki-Coupling of4-bromo-6-(4-(trifluoromethoxy)phenyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-onewith XII-8b. ¹H NMR (DMSO-d₆, 400 MHz) δ 12.93 (s, 1H), 12.27 (s, 1H),8.15 (s, 1H), 7.90 (s, 1H), 7.64 (d, J=8.4 Hz, 2H), 7.52 (d, J=8.4 Hz,2H), 7.41 (d, J=8.4 Hz, 2H), 6.67 (d, J=2.4 Hz, 1H). HCl salt compound604a: ¹H NMR (DMSO-d₆, 400 MHz) δ 12.28 (s, 1H), 8.06 (s, 2H), 7.64 (d,J=8.4 Hz, 2H), 7.52 (d, J=8.4 Hz, 2H), 7.42 (m, 2H), 6.67 (d, J=2.4 Hz,1H). MS (ESI) m/z (M+H)⁺ 361.0.

Compound 609 was obtained by Pd/C hydrogenation of4-bromo-6-(4-(trifluoromethoxy)phenyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-oneas a white solid. ¹H NMR (DMSO-d₆, 400 MHz) δ 12.15 (s, 1H), 7.59-7.57(m, 2H), 7.51-7.49 (m, 2H), 7.35 (t, J=2.6 Hz, 1H), 7.17 (d, J=7.2 Hz,1H), 6.62 (d, J=7.2 Hz, 1H), 6.37 (d, J=2.0 Hz, 1H). MS (ESI) m/z (M+H)⁺295.0.

Compound 610 was obtained by ethylation of Compound 609 using EtI in thepresence of Cs₂CO₃ in DMF. ¹H NMR (DMSO-d₆, 400 MHz) δ 7.57-7.55 (m,2H), 7.50-7.48 (m, 2H), 7.44 (d, J=2.4 Hz, 1H), 7.16 (d, J=7.2 Hz, 1H),6.56 (d, J=7.2 Hz, 1H), 6.33 (d, J=2.8 Hz, 1H), 4.46 (q, J=7.2 Hz, 2H),1.31 (t, J=7.2 Hz, 3H). MS (ESI) m/z (M+H)⁺ 322.9.

Other compounds were also prepared using the various proceduresdescribed in Example 5-F.

Compound 605: ¹H NMR (CDCl₃, 400 MHz) δ 10.73 (s, 1H), 7.73 (s, 1H),7.63 (s, 1H), 7.50 (d, J=8.4 Hz, 2H), 7.44 (d, J=8.4 Hz, 2H), 7.32 (s,1H), 7.08 (s, 1H), 6.57 (d, J=2.4 Hz, 1H), 3.98 (s, 3H). MS (ESI) m/z(M+H)⁺ 324.9.

Compound 606: ¹H NMR (DMSO-d₆, 400 MHz) δ 12.95 (s, 1H), 12.28 (s, 1H),8.15 (s, 1H), 7.90 (s, 1H), 7.61-7.54 (m, 4H), 7.43 (s, 1H), 7.37 (s,1H), 6.68 (d, J=2.0 Hz, 1H). HCl salt: MS (ESI) m/z (M+H)⁺ 310.9.

Compound 607: ¹H NMR (DMSO-d₆, 400 MHz) δ 12.93 (s, 1H), 12.21 (s, 1H),8.13-7.89 (m, 2H), 7.42-7.41 (m, 1H), 7.20-7.18 (m, 2H), 6.96-6.86 (m,2H), 6.68 (d, J=2.4 Hz, 1H), 4.08 (q, J=6.8 Hz, 2H), 2.04 (s, 3H), 1.36(t, J=6.8 Hz, 3H). MS (ESI) m/z (M+H)⁺ 334.9.

Compound 608: ¹H NMR (DMSO-d₆, 400 MHz) δ 12.37 (s, 1H), 8.07-8.02 (m,4H), 7.78 (d, J=8.8 Hz, 2H), 7.45 (d, J=8.8 Hz, 2H), 6.70 (d, J=2.4 Hz,1H). MS (ESI) m/z (M+H)⁺ 301.9.

Compound 611: ¹H NMR (DMSO-d₆, 400 MHz) δ 10.97 (s, 1H), 8.01 (s, 1H),7.71 (s, 1H), 7.41 (s, 1H), 6.98 (s, 1H), 6.50 (d, J=2.8 Hz, 1H), 4.51(q, J=6.8 Hz, 2H), 3.85 (s, 3H), 1.33 (t, J=6.8 Hz, 3H). MS (ESI) m/z(M+H)⁺ 242.9.

Compound 612: ¹H NMR (DMSO-d₆, 400 MHz) δ 12.08 (s, 1H), 11.03 (s, 1H),8.06 (s, 1H), 7.76 (s, 1H), 7.35 (s, 1H), 7.05 (d, J=5.6 Hz, 1H), 6.58(d, J=2.8 Hz, 1H), 3.87 (s, 3H). MS (ESI) m/z [M+H]⁺ 215.0.

Compound 613: ¹H NMR (DMSO-d₆, 400 MHz) δ 12.91 (s, 1H), 11.00 (d, J=3.6Hz, 1H), 8.05 (s, 1H), 7.81 (s, 1H), 7.43 (d, J=2.8 Hz, 1H), 7.03 (d,J=5.2 Hz, 1H), 6.53 (d, J=2.8 Hz, 1H), 4.54 (q, J=7.2 Hz, 2H), 1.36 (t,J=7.2 Hz, 3H). MS (ESI) m/z [M+H]⁺ 229.1.

Compound 616: ¹H NMR (DMSO-d₆, 400 MHz) δ 12.93 (s, 1H), 12.08 (s, 1H),11.05 (s, 1H), 7.96 (brs, 2H), 7.35 (d, J=2.8 Hz, 1H), 7.07 (s, 1H),6.60 (d, J=2.8 Hz, 1H). MS (ESI) m/z [M+H]⁺ 201.1.

Compound 647 was prepared following the similar procedure described inthe synthesis of compound 593 using benzyl bromide in place of ethylbromide in the reaction with XIII-4b. After Suzuki-Coupling withXIII-10, benzyl was replaced by isopropyl by reaction with KOtBufollowed by isopropyl iodide. A second Suzuki-Coupling with1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleafforded the final product. ¹H NMR (DMSO-d₆, 400 MHz) δ 8.13 (s, 1H),7.81 (s, 1H), 7.72 (d, J=3.2 Hz, 1H), 7.63 (d, J=8.8 Hz, 2H), 7.52 (d,J=8.8 Hz, 2H), 7.38 (s, 1H), 6.67 (d, J=3.2 Hz, 1H), 5.77-5.70 (m, 1H),3.88 (s, 3H), 1.44 (d, J=6.8 Hz, 6H). MS (ESI) m/z (M+H)⁺ 417.1.

Compound 648 was prepared following the similar procedure described inthe synthesis of Compound 647 using the Boc-protected boronic ester inthe last coupling reaction. ¹H NMR (DMSO-d₆, 400 MHz) δ 12.96 (s, 1H),8.14 (s, 1H), 7.89 (s, 1H), 7.71 (d, J=3.2 Hz, 1H), 7.64 (d, J=8.8 Hz,2H), 7.52 (d, J=8.8 Hz, 2H), 7.39 (s, 1H), 6.67 (d, J=3.2 Hz, 1H),5.77-5.71 (m, 1H), 1.44 (d, J=6.8 Hz, 6H). MS (ESI) m/z (M+H)⁺ 403.1.

Compounds 649 and 650 were prepared by Suzuki-Coupling of4-bromo-6-(4-(trifluoromethoxy)phenyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-onewith cyclopropylboronic acid then a second Suzuki Coupling with thecorresponding boronic esters. Compound 649: ¹H NMR (DMSO-d₆, 400 MHz) δ8.12 (s, 1H), 7.81 (s, 1H), 7.64 (d, J=8.8 Hz, 2H), 7.53 (d, J=8.8 Hz,2H), 7.46 (d, J=2.8 Hz, 1H), 7.38 (s, 1H), 6.57 (d, J=2.8 Hz, 1H),4.20-4.15 (m, 1H), 3.86 (s, 3H), 1.07-0.96 (m, 4H). MS (ESI) m/z (M+H)⁺415.0. Compound 650: ¹H NMR (DMSO-d₆, 400 MHz) δ 12.95 (brs, 1H), 8.13(s, 1H), 7.88 (s, 1H), 7.64 (d, J=8.8 Hz, 2H), 7.52 (d, J=8.8 Hz, 2H),7.38 (d, J=3.6 Hz, 1H), 7.40 (s, 1H), 6.58 (d, J=3.6 Hz, 1H), 4.19-4.14(m, 1H), 1.03-0.97 (m, 4H). MS (ESI) m/z (M+H)⁺ 401.1.

Compounds 651 and 654 were prepared by reacting4-bromo-6-(4-(trifluoromethoxy)phenyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-onewith 1-chloro-2-methoxyethane in the presence of Cs₂CO₃ in DMF, followedby Suzuki-Coupling with the corresponding boronic esters. Compound 651:¹H NMR (DMSO-d₆, 400 MHz) δ 8.13 (s, 1H), 7.82 (s, 1H), 7.64 (d, J=8.8Hz, 2H), 7.53 (d, J=8.8 Hz, 2H), 7.50 (d, J=3.2 Hz, 1H), 7.39 (s, 1H),6.61 (d, J=3.2 Hz, 1H), 4.66 (t, J=5.6 Hz, 2H), 3.88 (s, 3H), 3.66 (t,J=5.6 Hz, 2H), 3.23 (s, 3H). MS (ESI) m/z (M+H)⁺ 433.1. Compound 654: ¹HNMR (DMSO-d₆, 300 MHz) δ 12.96 (brs, 1H), 8.03 (brs, 2H), 7.63 (d, J=9.0Hz, 2H), 7.51 (d, J=3.0 Hz, 1H), 7.49 (d, J=9.0 Hz, 2H), 7.41 (s, 1H),6.61 (d, J=3.0 Hz, 1H), 4.66 (t, J=5.4 Hz, 2H), 3.65 (t, J=5.4 Hz, 2H),3.23 (s, 3H). MS (ESI) m/z (M+H)⁺ 419.1.

Compounds 652 and 653 were prepared by reacting4-bromo-6-(4-(trifluoromethoxy)phenyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-onewith 1-bromo-2-fluoroethane in the presence of Cs₂CO₃ in DMF, followedby Suzuki-Coupling with the corresponding boronic esters. Compound 652:¹H NMR (DMSO-d₆, 400 MHz) δ 12.96 (brs, 1H), 8.03 (brs, 2H), 7.64 (d,J=8.4 Hz, 2H), 7.53 (d, J=2.8 Hz, 1H), 7.52 (d, J=8.8 Hz, 2H), 7.44 (s,1H), 6.66 (d, J=2.8 Hz, 1H), 4.85-4.75 (m, 3H), 4.69 (m, 1H). MS (ESI)m/z (M+H)⁺ 407.1. Compound 653: ¹H NMR (DMSO-d₆, 400 MHz) δ 8.14 (s,1H), 7.83 (s, 1H), 7.64 (d, J=8.8 Hz, 2H), 7.53 (d, J=2.8 Hz, 1H), 7.52(d, J=8.8 Hz, 2H), 7.42 (s, 1H), 6.65 (d, J=2.8 Hz, 1H), 4.84-4.77 (m,3H), 4.69 (m, 1H), 3.87 (s, 3H). MS (ESI) m/z (M+H)⁺ 421.1.

Compound 655 was prepared following the similar procedure described inthe synthesis of compound 593 where 1-(difluoromethoxy)-4-iodobenzenewas used in place of XIII-10, and CuI, Cs₂CO₃, and 8-hydroxyquinoline inDMSO/dioxane used as the reaction catalysts. The reaction mixture waspurged with N₂ and stirred at 110° C. overnight. In the last stepcoupling reaction, Pd-118 and K₃PO₄ were used in place of Pd(dppf)Cl₂and K₂CO₃. ¹H NMR (DMSO-d₆, 400 MHz) δ 8.10 (s, 1H), 7.79 (s, 1H),7.54-7.51 (m, 3H), 7.32-7.14 (m, 4H), 6.59 (d, J=2.8 Hz, 1H), 4.51 (q,J=7.2 Hz, 2H), 3.85 (s, 3H), 1.33 (t, J=7.2 Hz, 3H).

Compound 691 was prepared following the similar procedure described inthe synthesis of Compound 593 using4-bromo-1-(2-ethoxyethyl)-6-(4-(trifluoromethoxy)phenyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-onein place of XIII-8b. ¹H NMR (CDCl₃, 400 MHz) δ 7.83 (br. s., 2H), 7.51(d, J=8.5 Hz, 2H), 7.36 (d, J=8.5 Hz, 2H), 7.29 (d, J=2.5 Hz, 1H), 7.08(s, 1H), 6.47 (d, J=2.3 Hz, 1H), 4.76 (t, J=4.9 Hz, 2H), 3.81 (t, J=4.9Hz, 2H), 3.45 (q, J=6.9 Hz, 2H), 1.15 (t, J=6.9 Hz, 3H). MS (ESI) m/z(M+H)⁺ 433.1.

Compound 692 was prepared following the similar procedure described inthe synthesis of Compound 593 using4-bromo-1-(2-isopropoxyethyl)-6-(4-(trifluoromethoxy)phenyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-onein place of XIII-8b. ¹H NMR (CDCl₃, 400 MHz) δ 7.85 (br.s., 2H), 7.52(d, J=8.4 Hz, 2H), 7.36 (d, J=8.4 Hz, 2H), 7.31 (d, J=2.4 Hz, 1H), 7.08(s, 1H), 6.46 (d, J=2.4 Hz, 1H), 4.74 (t, J=4.8 Hz, 2H), 3.79 (t, J=4.8Hz, 2H), 3.52-3.45 (m, 1H), 1.09 (d, J=6.0 Hz, 6H).

Compound 693 was prepared by the Suzuki-coupling of4-bromo-6-(4-(trifluoromethoxy)phenyl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-7(6H)-one with1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolecatalyzed by Pd-118/K₃PO₄ in dioxane/H₂O mixture; followed by reactionwith acetyl chloride to afford the final product. ¹H NMR (CDCl₃, 400MHz) δ 7.53 (s, 1H), 7.49-7.45 (m, 2H), 7.42 (s, 1H), 7.40-7.34 (m, 2H),7.28 (s, 1H), 4.28 (t, J=8.2 Hz, 2H), 3.95 (s, 3H), 3.04 (t, J=8.2 Hz,2H), 2.36 (s, 3H).

XIII-7 (2.5 g, 11 mmol) was dissolved in DCM (20 mL), then DMAP (98 mg,0.66 mmol) and Boc₂O (2.87 g, 13 mmol) was added. The mixture wasstirred at 25° C. for 1 h, then the solvent was removed in vacuo to giveXIII-11 (3.3 g, yield 91.6%).

XIII-11 (4 g, 12.2 mmol) was dissolved in MeOH (40 mL), then Pd/C (400mg, 10%) was added. The mixture was purged with hydrogen for three timesand then stirred at 70° C. for 40 h. Then the solvent was removed invacuo to give XIII-12 (3.1 g, yield 77%) as a white solid.

XIII-12 (3.3 g, 10.3 mmol) was dissolved in HCl-MeOH (4 M, 30 mL). Themixture was stirred at 70° C. for 2 h. Then the solvent was removed invacuo to give XIII-13 (2.1 g, yield 97%) as a white solid.

XIII-13 (1.5 g, 6.9 mmol) was dissolved in sat. aq. NaHCO₃ (20 mL) andMeOH/H₂O (v/v=1/1, 20 mL), then DMAP (102 mg, 0.69 mmol) and Boc₂O (2.27g, 1.0 mmol) was added. The mixture was stirred at 25° C. for 48 h. Thenthe mixture was extracted with EA, the combined organic phase was driedover anhydrous Na₂SO₄, filtered, concentrated in vacuo to afford ayellowish solid. The crude product was purified to give XIII-14 (380 mg,16.8%) as a white solid.

XIII-14 was reacted with XIII-10 following the standard proceduredescribed herein to give Compound 690 (230 mg, 41.7%) as a white solid.¹HNMR (CDCl₃, 400 MHz) δ 7.51 (s, 1H), 7.44 (d, J=8.5 Hz, 2H), 7.39 (s,1H), 7.32 (d, J=8.5 Hz, 2H), 7.20 (s, 1H), 4.11 (t, J=8.3 Hz, 2H), 3.93(s, 3H), 3.05 (t, J=8.3 Hz, 2H), 1.52 (s, 9H). MS (ESI) m/z (M+H)⁺477.2.

Example 5-G Synthesis of Compounds 50-53 (Scheme XIV)

XIV-1 (10 g, 64.1 mmol) was added into POCl₃ (20 mL), the reactionmixture was heated at reflux for 2 hrs. The mixture was cooled to rt andpoured into saturated aqueous Na₂CO₃, the mixture was extracted withEtOAc. The combined organic phase was dried over Na₂SO₄, andconcentrated under reduced pressure. The residue was purified by columnchromatography (PE:EA=10:1) to afford XIV-2 as a pale yellow solid (10g, 83% yield). ¹HNMR (CDCl₃, 300 MHz) δ 8.45 (d, J=5.4 Hz, 1H), 7.48 (d,J=5.4 Hz, 1H).

To a solution of XIV-2 (10 g, 52.1 mmol) in DMF (60 mL) was added NaOAc(10.3 g, 125 mmol), the reaction mixture was stirred at 120° C. for 3hrs. The mixture was cooled to rt and poured into water, extracted withEtOAc. Combined organic phase was washed with brine and concentratedunder vacuum to afford the crude product. The residue was purified bycolumn chromatography (PE:EA=1:1) to afford XIV-3 as a pale yellow solid(5.4 g, 60% yield). ¹HNMR (CD₃OD, 300 MHz) δ 8.14 (d, J=6.0 Hz, 1H),6.98 (d, J=6.0 Hz, 1H).

To a solution of XIV-3 (5.4 g, 31.03 mmol) in DMF (30 mL) was addedNaOMe (8.4 g, 155.17 mmol), the reaction mixture was stirred at 80° C.for 10 hrs. The mixture was cooled to rt and poured into water,extracted with EtOAc. Combined organic phase was washed with brine andconcentrated under vacuum to afford the crude product. The residue waspurified by column chromatography (PE:EA=1:1) to afford XIV-4 as a paleyellow solid (4.5 g, 85% yield). ¹HNMR (CDCl₃, 300 MHz) δ 11.48 (brs,1H), 8.10 (d, J=5.7 Hz, 1H), 6.71 (d, J=5.7 Hz, 1H), 4.11 (s, 3H).

To a suspension of XIV-4 (4.5 g, 26.47 mmol) in water (30 mL) were addeddrop wise Br₂ (5.3 g, 33.35 mmol) at rt, the reaction mixture wasstirred for 30 min then heated at 50° C. for 1 h. After cooling to rt,the mixture was filtered, washed with water and dried under vacuum toyield XIV-5 as a pale yellow solid. (3.0 g, 46% yield). ¹HNMR (CDCl₃,400 MHz) δ 8.29 (s, 1H), 4.08 (s, 3H).

A flask was charged with XIV-5 (2.49 g, 10 mmol, 1 eq.), XIV-6 (1.25 g,12 mmol, 1.2 eq.), PPh₃ (3.14 g, 12 mmol, 1.2 eq.) and 30 mL ofanhydrous THF, flushed with nitrogen for three times. DIAD (2.42 g, 12mmol, 1.2 eq.) was added drop wise into the mixture at 0° C. After that,the mixture was warmed to rt and stirred for another 16 hrs. TLC(PE:EA=5:1) analysis showed the reaction completed. The mixture wasdiluted with water, extracted with EtOAc (100 mL×3). The combinedorganic layer was washed with brine, dried over Na₂SO₄, filtered andconcentrated to give a yellow oil. Purification by column chromatographygave XIV-7 (3 g, yield 89%). ¹H NMR (CDCl₃, 300 MHz): δ 8.33 (s, 1H),4.82 (s, 2H), 4.27 (q, J=7.2 Hz, 2H), 4.02 (s, 3H), 1.30 (t, J=7.2 Hz,3H).

A flask was charged with XIV-7 (3 g, 8.96 mmol, 1 eq.), Fe powder (2 g,35.82 mmol, 4 eq.) and 40 mL of AcOH. The mixture was heated at 80° C.for 3 hrs. TLC (PE:EA=3:1) analysis showed the reaction completed. Themixture was cooled down to rt, adjusted pH=7-8 with saturated aq. K₃PO₄,extracted with EtOA (100 mL×3). The combined organic layer was washedwith brine, dried over Na₂SO₄, filtered and concentrated to give ayellow oil. Purification by column chromatography gave XIV-8 (1.5 g, 65%yield). MS (ESI) m/z (M+H)⁺ 260.8

To a solution of XIV-8 (1 g, 3.86 mmol, 1 eq.) in 15 mL of DMF was addedNaH (60%, 185 mg, 4.63 mmol, 1.2 eq.) at 0° C. The mixture was stirredat 0° C. for 30 min. After that, BnBr (792 mg, 4.63 mmol, 1.2 eq.) wasadded. The resulting mixture was stirred for 16 hrs at rt. TLC(PE:EA=3:1) analysis showed the reaction completed. The mixture wasdiluted with water, extracted with EtOA (80 mL×3). The combined organiclayer was washed with brine, dried over Na₂SO₄, filtered andconcentrated to give yellow oil. Purification by column chromatographygave XIV-9 (1.2 g, 89% yield). MS (ESI) m/z (M+H)⁺ 350.9.

To a solution of XIV-9 (50 mg, 0.14 mmol, 1 eq.) in 6 mL of EtOH wasadded 1 mL of aq. HBr (40%). The mixture was heated at 100° C. for 1 h.TLC (EA) analysis showed the reaction completed. The mixture was cooleddown to rt, adjusted pH=7-8 with saturated aq. NaHCO₃, extracted withEtOA (50 mL×3). The combined organic layer was washed with brine, driedover Na₂SO₄, filtered and concentrated to give XIV-10 (45 mg, 95%yield). ¹H NMR (CDCl₃, 400 MHz): δ 12.49 (brs, 1H), 7.26-7.22 (m, 6H),5.64 (s, 2H), 4.73 (s, 2H).

The preparation of XIV-12 was followed the general procedure asdescribed in the synthesis of X-6.

Compound 50 was prepared following the similar procedure for obtainingCompound 40 using1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole inreplace of X-7. ¹H NMR (CDCl₃, 300 MHz) δ 7.56 (s, 1H), 7.51 (s, 1H),7.30-7.17 (m, 11H), 5.58 (s, 2H), 4.65 (s, 2H), 3.86 (s, 3H). MS (ESI)m/z [M+H]⁺ 496.9.

Compound 51 was prepared following the similar procedure for obtainingCompound 40. ¹H NMR (CDCl₃, 300 MHz) δ 7.29-7.19 (m, 11H), 7.05-7.02 (m,3H), 5.59 (s, 2H), 4.60 (s, 2H). MS (ESI) m/z [M+H]⁺ 511.2.

Compound 52: A flask was charged with Compound 51 (340 mg, 0.67 mmol),Pd/C (34 mg, 10% mol) and 10 mL of EtOH. The mixture was stirred for 30hrs under hydrogen (50 psi). TLC (PE: EA=1:1) analysis showed thereaction completed. The mixture was filtered; the filtrate wasconcentrated to give yellow solid. Purification by prep-TLC gaveCompound 52 (190 mg, 68% yield). ¹H NMR (CDCl₃, 400 MHz) δ 8.07 (s, 1H),7.49 (d, J=8.8 Hz, 2H), 7.40-7.38 (m, 4H), 7.12-7.10 (m, 3H), 4.74 (s,2H). MS (ESI) m/z [M+H]⁺ 421.2.

Compound 53: To a solution of Compound 52 (100 mg, 0.24 mmol, 1 eq.) in5 mL of DMF was added NaH (14 mg, 0.54 mmol, 1.5 eq.) at 0° C. Themixture was stirred at 0° C. for 30 min. After that, MeI (50.7 mg, 0.54mmol, 1.5 eq.) was added into the flask. The resulting mixture wasstirred for 16 hrs at rt. TLC (PE: EA=1:1) analysis showed the reactioncompleted. The mixture was diluted with water, extracted with EtOAc (50mL×3). The combined organic layer was washed with brine, dried overNa₂SO₄, filtered and concentrated to give yellow oil. Purification byprep-TLC gave Compound 53 (55.5 mg, 54% yield). ¹H NMR (CDCl₃, 300 MHz)δ 7.51-7.48 (m, 2H), 7.42-7.37 (m, 4H), 7.22 (s, 1H), 7.16-7.13 (m, 2H),4.63 (s, 2H), 3.61 (s, 3H).

To a solution of XIV-8 (200 mg, 0.77 mmol, 1 eq.) in 10 mL of DMF wasadded NaH (60% dispersion in mineral oil, 60 mg, 1.16 mmol, 1.5 eq.) at0° C. The mixture was stirred at 0° C. for 30 min. After that, PMBC (181mg, 1.16 mmol, 1.5 eq.) was added into the flask. The resulting mixturewas stirred for another 16 hrs at rt. TLC (PE/EA=3/1) analysis showedthe reaction completed. The mixture was diluted with water (20 mL),extracted with EtOA (30 mL×3). The combined organic layer was washedwith brine, dried over Na₂SO₄, filtered and concentrated to give yellowoil. Purification by prep-TLC (PE/EA=3/1) yield XIV-9a (245 mg, 85%yield). MS (ESI) m/z (M+H)⁺ 379.0.

XIV-12a was prepared following the scheme illustrated above. MS (ESI)m/z (M+H)⁺ 526.9.

The mixture of XIV-12a (100 mg, 0.19 mmol) and 5 mL of TFA was heated at80° C. for 6 hrs. TLC (EA) analysis showed the reaction completed. Themixture was cooled down to rt, most of TFA was evaporated, the residuewas neutralized with saturated aq.NaHCO₃, extracted with EtOAc (50mL×3). The combined organic layer was washed with brine, dried overNa₂SO₄, filtered, concentrated to give a yellow solid. Purification byprep-TLC (EA) gave Compound 393 (72.3 mg, 93% yield). ¹H NMR (CDCl₃, 400MHz) δ 8.06 (brs, 1H), 7.67 (s, 1H), 7.63 (s, 1H), 7.48-7.45 (m, 2H),7.38-7.35 (m, 2H), 7.22 (s, 1H), 4.81 (s, 2H), 3.95 (s, 3H). MS (ESI)m/z (M+H)⁺406.9.

Compound 396 was prepared following the similar procedure for obtainingXIV-12a using methyl iodide in place of PMBC. ¹H NMR (CDCl₃, 400 MHz) δ7.64-7.61 (m, 2H), 7.47-7.45 (m, 2H), 7.39-7.37 (m, 2H), 7.31 (s, 1H),4.67 (s, 2H), 3.95 (s, 3H), 3.58 (s, 3H). MS (ESI) m/z [M+H]⁺ 420.9.

XIV-5b was obtained from XIV-3 in two steps by bromination andSuzuki-Coupling with (4-fluorophenyl)boronic acid using the standardprocedure described herein.

A solution of XIV-5b (1.5 g, 5.6 mmol) in conc.HCl/AcOH (14 mL, v/v=1/1)was heated at reflux overnight. After cooling to r.t, the mixture wasconcentrated under reduced pressure to give XIV-6b without furtherpurification (1.1 g, 78% yield).

XIV-6b (1.1 g, 4.4 mmol) was added into aq.NaOH (15 mL, 1M). ThenNa₂S₂O₄ (1.5 g, 8.8 mmol) was added. The mixture was stirred at rt.under dark for 1 h. After completion of the reaction indicated by TLC(PE/EA=1:2), the mixture was acidified to pH=5-6, then extracted withEA. The organic layer was washed with brine, dried over Na₂SO₄,concentrated in vacuo to give XIV-7b without further purification (0.8g, 83% yield).

A mixture of XIV-7b (0.8 g, 3.6 mmol) in CH₃C(OEt)₃ (10 mL) was heatedat reflux overnight. After cooling to rt, the mixture was filtered, thefiltrate cake was washed with EA/PE (1:1) to give crude XIV-8b (340 mg,39% yield).

Compound 568 was obtained by Suzuki-Coupling of XIV-8b with XIV-11 usingstandard procedure described herein. ¹H NMR (Methanol-d₄, 300 MHz) δ7.78 (s, 1H), 7.72-7.67 (m, 2H), 7.55-7.51 (m, 2H), 7.41 (d, J=8.4 Hz,2H), 7.16-7.10 (m, 2H), 2.59 (s, 3H).

Example 5-H Synthesis of Compounds 54-59 (Scheme XV)

To a solution of XV-1 (15 g, 96.2 mmol) in AcOH (120 mL) were added Br₂(16.7 g, 105.8 mmol). After addition, the reaction mixture was stirredat 70° C. for 30 min. Then the reaction mixture was poured intoice-water, the resulting precipitate was collected by filtration, washedwith water and dried in reduced pressure to afford XV-2 as a yellowsolid (14 g, 60% yield). ¹H NMR (DMSO-d₆, 400 MHz) δ 7.85 (s, 1H).

XV-2 (2 g, 8.5 mmol) was added into POCl₂OPh (10 mL), and then thereaction mixture was heated at refluxed for 2 hrs. The mixture wascooled to rt and neutralize with saturated aq. Na₂CO₃, the mixture wasextracted with EtOAc. The combined organic phase was dried over Na₂SO₄,and concentrated under reduced pressure. The residue was purified bycolumn chromatography (PE:EA=10:1) to afford XV-3 as a pale yellowsolid. (1.5 g, 65% yield). ¹HNMR (CDCl₃, 300 MHz) δ 8.71 (s, 1H).

To a solution of XV-3 (544 mg, 2 mmol) in 10 mL of DMF was added BnNH₂(268 mg, 2 mmol) at 0° C. The mixture was stirred for 18 h at rt. TLC(PE: EA=5:1) analysis showed the reaction completed. The mixture wasdiluted with water, extracted with EtOAc (30 mL×3). The combined organiclayer was washed with brine, dried over Na₂SO₄, filtered, concentratedto give yellow oil. Purification by column chromatography gave XV-4 as awhite solid (400 mg, 58% yield). MS (ESI) m/z [M+H]⁺ 342.2.

To a solution of XV-4 (200 mg, 0.58 mmol, 1 eq.) in 6 mL of AcOH wasadded Fe powder (131 mg, 2.34 mmol, 4 eq.). The mixture was heated at70-80° C. and stirred for 3 hrs. TLC (PE: EA=5:1) analysis showed thereaction completed. The mixture was cooled down to rt, neutralized withsaturated aq. K₃PO₄, extracted with EtOAc (50 mL×3). The combinedorganic layer was washed with brine, dried over Na₂SO₄, filtered,concentrated to give yellow oil. Purification by prep-TLC gave crudeXV-5 (182 mg, 100% crude yield). MS (ESI) m/z (M+H)⁺ 313.9.

The mixture of XV-5 (1.5 g, 4.8 mmol, 1 eq) and 20 mL of formic acid washeated at 100° C. for 18 hrs. The reaction mixture was cooled down tort, neutralized with saturated aq. K₃PO₄, extracted with EtOAc (100mL×3). The combined organic layer was washed with brine, dried overNa₂SO₄, filtered, concentrated to give XV-6 (1.2 g, 82% yield). MS (ESI)m/z (M+H)⁺304.0.

The preparation of XV-8 followed the similar procedure for obtaining X-6(1.1 g, 61% yield). MS (ESI) m/z (M+H)⁺ 465.9.

Compound 54 was prepared following the similar procedure for obtainingCompound 40. ¹H NMR (CDCl₃, 300 MHz) δ 7.75 (s, 1H), 7.44 (d, J=8.1 Hz,2H), 7.26-6.90 (m, 10H), 6.55-6.50 (m, 2H), 4.92 (s, 2H). MS (ESI) m/z(M+H)⁺ 480.2.

Compound 55 was prepared following the similar procedure for obtainingCompound 40 using1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole inreplace of X-7. ¹H NMR (CDCl₃, 300 MHz) δ 7.73 (s, 1H), 7.44-7.41 (m,2H), 7.32-7.19 (m, 6H), 6.92 (s, 1H), 6.73-6.63 (m, 3H), 5.05 (s, 2H),3.70 (s, 3H). MS (ESI) m/z (M+H)⁺ 466.0.

XV-11: A flask was charged with XV-10, Pd/C (10% mol) and EtOH. Themixture was stirred for 24 hrs under hydrogen (50 psi). TLC (PE: EA=1:1)analysis showed the reaction completed. The mixture was filtered; thefiltrate was concentrated to give a yellow solid. Purification byprep-TLC gave XV-11.

Compound 56 was prepared from the Pd/C catalytic hydrogenation ofCompound 54. ¹H NMR (DMSO-d₆, 400 MHz): δ 13.74 (s, 1H), 8.32 (s, 1H),8.12-8.09 (m, 2H), 7.73-7.67 (m, 3H), 7.57-7.54 (m, 2H), 7.28-7.23 (m,2H). MS (ESI) m/z (M+H)⁺ 390.0.

Compound 57 was prepared from the catalytic hydrogenation of Compound55. ¹H NMR (CDCl₃, 400 MHz): δ 12.39 (s, 1H), 8.33 (s, 1H), 8.09 (s,2H), 7.82 (s, 1H), 7.55 (d, J=8.8 Hz, 2H), 7.45-7.41 (m, 2H), 3.99 (s,3H). MS (ESI) m/z (M+H)⁺ 376.0.

XV-12: To a solution of XV-11 (1 eq.) in DMF was added NaH (1.5 eq.) at0° C. The mixture was stirred at 0° C. for 30 min. After that, MeI (1.5eq.) was added. The resulting mixture was stirred for 16 hrs at rt. TLC(PE: EA=1:1) analysis showed the reaction completed. The mixture wasdiluted with water, extracted with EtOAc. The combined organic layer waswashed with brine, dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by prep-HPLC to yield XV-12.

Compound 58 was prepared by reacting Compound 56 with NaH in DMFfollowed by MeI. ¹H NMR (CDCl₃, 400 MHz): δ 7.90-7.75 (m, 3H), 7.56-7.13(m, 7H), 4.19 (s, 3H). MS (ESI) m/z (M+H)⁺ 404.0.

Compound 59 was prepared from Compound 57. ¹H NMR (CDCl₃, 400 MHz): δ8.26 (s, 1H), 7.86 (s, 1H), 7.79 (s, 1H), 7.50 (d, J=8.8 Hz, 2H),7.40-7.33 (m, 3H), 4.17 (s, 3H), 3.97 (s, 3H). MS (ESI) m/z (M+H)⁺390.1.

Alternative Synthesis of Compound 59

The alternative synthesis of Compound 59 was performed according to thestandard procedure as described herein. HCl salt compound 59a: ¹H NMR(DMSO-d₆, 400 MHz) δ 8.43 (s, 1H), 7.97 (s, 1H), 7.67 (s, 1H), 7.63 (d,J=8.8 Hz, 2H), 7.54 (d, J=8.8 Hz, 2H), 7.38 (s, 1H), 3.89 (s, 3H), 3.61(s, 3H). MS (ESI) m/z (M+H)⁺ 390.1.

Compound 636 was prepared following a modified synthetic route whereXV-3 was reacted with ethylamine instead of benzy amine, followed bytwo-step Suzuki-Coupling reactions. Pd-118, K₃PO₄ were used in place ofPd(dppf)Cl₂ and K₂CO₃. ¹H NMR (DMSO-d₆, 400 MHz): δ 8.14 (s, 1H), 7.96(s, 1H), 7.66 (s, 1H), 7.61 (d, J=8.4 Hz, 2H), 7.51 (d, J=8.4 Hz, 2H),7.26 (s, 1H), 4.01 (q, J=7.2 Hz, 2H), 3.88 (s, 3H), 1.06 (t, J=7.2 Hz,3H).

Compound 637 was prepared by Suzuki-Coupling of a modified XV-5 (wherebenzyl is replaced by ethyl) with1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole,followed by reaction with HCOOH. ¹H NMR (DMSO-d₆, 400 MHz) δ 12.2 (s,1H), 9.17 (s, 1H), 7.96 (s, 1H), 7.63 (s, 1H), 7.19 (s, 1H), 4.04 (q,J=7.2 Hz, 2H), 3.91 (s, 3H), 1.11 (t, J=7.2 Hz, 3H).

Compound 638 was prepared following the same procedure for the synthesisof Compound 637 using the Boc-protected bononic ester. ¹H NMR (DMSO-d₆,400 MHz) δ 9.41 (s, 1H), 7.94 (s, 2H), 7.38 (s, 1H), 4.16 (q, J=7.2 Hz,2H), 1.28 (t, J=7.2 Hz, 3H).

Compound 640 was prepared following the same procedure for the synthesisof Compound 636 with a Boc-protected boronic ester in place in the lastSuzuki-Coupling reaction. ¹H NMR (DMSO-d₆, 400 MHz): δ 13.07 (brs, 1H),8.14 (s, 1H), 8.02 (s, 1H), 7.72 (s, 1H), 7.61 (d, J=8.8 Hz, 2H), 7.51(d, J=8.8 Hz, 2H), 7.26 (s, 1H), 3.97 (q, J=7.2 Hz, 2H), 1.02 (t, J=7.2Hz, 3H). HCl salt Compound 640a: ¹H NMR (DMSO-d₆, 400 MHz): δ 8.76 (s,1H), 7.91 (s, 2H), 7.65 (d, J=8.8 Hz, 2H), 7.55 (d, J=8.8 Hz, 2H), 7.46(s, 1H), 4.05 (q, J=6.8 Hz, 2H), 1.08 (t, J=6.8 Hz, 3H).

Compound 641 was prepared by Pd/C hydrogenation (50 psi) of XV-8 inethanol at 40° C. overnight. ¹H NMR (DMSO-d₆, 400 MHz) δ 8.58 (s, 1H),7.62-7.54 (m, 6H), 6.78 (d, J=7.2 Hz, 1H). HCl salt compound 641a: ¹HNMR (DMSO-d₆, 400 MHz) δ 8.01 (s, 1H), 7.68-7.54 (m, 6H), 6.83 (d, J=6.4Hz, 1H).

Compound 639 was prepared by Pd/C hydrogenation of a modified XV-8(wherein benzyl is replaced by ethyl). ¹H NMR (DMSO-d₆, 400 MHz): δ 8.14(s, 1H), 7.55 (m, 5H), 6.83 (d, J=7.6 Hz, 1H), 4.23 (q, J=6.8 Hz, 2H),1.40 (t, J=6.8 Hz, 3H). HCl salt compound 639a: ¹H NMR (DMSO-d₆, 400MHz): δ 8.69 (s, 1H), 7.69 (d, J=7.6 Hz, 1H), 7.61-7.54 (m, 4H), 6.96(d, J=7.6 Hz, 1H), 4.31 (q, J=7.2 Hz, 2H), 1.43 (t, J=7.2 Hz, 3H).

Alternatively, Compound 639 can be prepared from reacting Compound 641with NaH followed by reacting with ethyl iodide.

Compound 642 was prepared by Suzuki-Coupling of XV-8 with1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolefollowed by deprotection of the benzyl group using KOt-Bu in DMSO. ¹HNMR (DMSO-d6, 300 MHz): δ 8.46 (s, 1H), 8.32 (s, 1H), 8.11 (s, 1H), 7.78(s, 1H), 7.69 (d, J=8.7 Hz, 2H), 7.58 (d, J=8.7 Hz, 2H), 4.17 (t, J=7.2Hz, 2H), 1.41 (t, J=7.2 Hz, 3H).

Compound 643 was prepared by Suzuki-Coupling of XV-8 with1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolefollowed by deprotection of the benzyl group using KOt-Bu in DMSO. ¹HNMR (DMSO-d₆, 400 MHz): δ 13.63 (brs, 1H), 8.46 (s, 1H), 8.30 (s, 1H),8.12 (s, 1H), 7.77 (s, 1H), 7.67 (d, J=8.4 Hz, 2H), 7.57 (d, J=8.4 Hz,2H), 4.52 (m, 2H), 1.44 (d, J=6.4 Hz, 6H).

Compound 644 was prepared by Suzuki-Coupling of a modified XV-8 (whereinbenzyl is replaced by methyl) with1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleusing Pd-118 and K₃PO₄ in dioxane/H₂O refluxing for 8 h. ¹H NMR(DMSO-d₆, 400 MHz): δ 8.06 (s, 1H), 8.00 (s, 1H), 7.66 (s, 1H), 7.60 (d,J=8.8 Hz, 2H), 7.51 (d, J=8.8 Hz, 2H), 7.28 (s, 1H), 4.16 (q, J=7.2 Hz,2H), 3.55 (s, 3H), 1.40 (t, J=8.8 Hz, 3H).

Compound 645 was prepared by Suzuki-Coupling of a modified XV-8 (whereinbenzyl is replaced by methyl) with1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleusing Pd-118 and K₃PO₄ in dioxane/H₂O refluxing for 8 h. ¹H NMR(DMSO-d₆, 400 MHz): δ 8.04 (d, J=7.2 Hz, 2H), 7.65 (s, 1H), 7.61 (d,J=8.8 Hz, 2H), 7.53 (d, J=8.8 Hz, 2H), 7.29 (s, 1H), 4.52 (m, 1H), 3.55(s, 3H), 1.44 (d, J=6.8 Hz, 6H).

Compound 646 was prepared by Suzuki-Coupling of XV-8 with1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole,then KOt-Bu deprotecting of the benzyl group, followed by deprotonationwith NaH in DMF, then reaction with 1-bromo-2-fluoroethane. ¹H NMR(DMSO-d6, 300 MHz) δ 8.44 (s, 1H), 8.39 (s, 1H), 8.09 (s, 1H), 7.84 (s,1H), 7.68 (d, J=8.7 Hz, 2H), 7.57 (d, J=8.7 Hz, 2H), 4.90 (m, 1H), 4.82(m, 1H), 4.74 (s, 2H), 3.89 (s, 3H).

Compound 665 was prepared by Suzuki-Coupling of XV-8 with1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole,then KOt-Bu deprotecting of the benzyl group, followed by deprotonationwith NaH in DMF, then reacting with Md. ¹H NMR (DMSO-d₆, 400 MHz) δ 8.43(s, 1H), 8.30 (s, 1H), 8.08 (s, 1H), 7.78 (s, 1H), 7.64 (d, J=8.8 Hz,2H), 7.55 (d, J=8.8 Hz, 2H), 4.05 (s, 3H), 3.88 (s, 3H). MS (ESI) m/z(M+H)⁺ 390.1.

Compound 669 was prepared by reacting7-bromo-3-ethyl-3H-imidazo[4,5-c]pyridin-4(5H)-one with XV-7 followingthe standard copper acetate/pyridine/pyridine-N-oxide catalyzed reactionin DMF at 100° C. to form7-bromo-3-ethyl-5-(4-(trifluoromethoxy)phenyl)-3H-imidazo[4,5-c]pyridin-4(5H)-one,followed by Suzuki-couling with tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate,catalyzed by Pd-118/K₃PO₄ in dioxane/H₂O mixture under reflux conditionto provide the final product. ¹H NMR (DMSO-d₆, 400 MHz) δ 12.86 (brs,1H), 8.43 (brs, 1H), 8.36 (s, 1H), 8.17 (brs, 1H), 7.80 (s, 1H), 7.65(d, J=8.4 Hz, 2H), 7.54 (d, J=8.4 Hz, 2H), 4.45 (q, J=7.2 Hz, 2H), 1.40(t, J=7.2 Hz, 3H). MS (ESI) m/z [M+H]⁺ 390.1.

Compound 670 was prepared by reacting Compound 642 with ethyl iodidewith the presence of NaH in DMF solution at rt for 2 hrs. ¹H NMR (CDCl₃,400 MHz) δ 8.29 (s, 1H), 7.92 (s, 1H), 7.82 (s, 1H), 7.51 (d, J=8.8 Hz,2H), 7.38 (d, J=8.8 Hz, 2H), 7.37 (s, 1H), 4.56 (q, J=7.2 Hz, 2H), 4.24(q, J=7.2 Hz, 2H), 1.59-1.51 (m, 6H). MS (ESI) m/z [M+H]⁺ 418.1.

Compound 671 was prepared by reacting Compound 643 with ethyl iodide inthe presence of NaH in DMF solution at rt for 2 hrs. ¹H NMR (CDCl₃, 300MHz) δ 8.33 (s, 1H), 7.95 (s, 1H), 7.86 (s, 1H), 7.53 (d, J=8.4 Hz, 2H),7.41 (d, J=8.4 Hz, 2H), 7.39 (s, 1H), 4.62-4.55 (m, 3H), 1.60-1.55 (m,9H). MS (ESI) m/z [M+H]⁺ 431.9.

Compound 673 was prepared by reacting Compound 643 with methyl iodide inthe presence of NaH in DMF solution at rt for 2 hrs. ¹H NMR (CDCl₃, 300MHz): δ 8.29 (s, 1H), 7.84 (d, J=10.0 Hz, 2H), 7.41 (d, J=8.4 Hz, 2H),7.49 (d, J=9.2 Hz, 2H), 7.38-7.34 (m, 3H), 4.57-4.52 (m, 1H), 4.16 (s,3H), 1.47 (s, 3H), 1.45 (s, 3H). MS (ESI) m/z [M+H]⁺ 418.1.

Compound 672 was prepared by reacting XV-8 with tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylatecatalyzed by Pd-118/K₃PO₄ in dioxane/H₂O mixture under reflux conditionovernight, followed by removal of the benzyl protecting group usingt-BuOK in DMSO/THF at rt for 1 h under oxygen atmosphere. MS (ESI) m/z[M+H]⁺ 361.9. ¹H NMR (DMSO-d₆, 400 MHz) δ 13.66 (brs, 1H), 12.87 (brs,1H), 8.45 (brs, 1H), 8.31 (brs, 1H), 8.19 (brs., 1H), 7.79 (brs, 1H),7.66 (d, J=8.5 Hz, 2H), 7.54 (d, J=8.5 Hz, 2H).

Compound 674 was prepared by reacting7-bromo-1,2-dimethyl-1H-imidazo[4,5-c]pyridin-4(5H)-one with XV-7following the standard copper acetate/pyridine/pyridine-N-oxidecatalyzed reaction in DMF at 100° C. to form7-bromo-1,2-dimethyl-5-(4-(trifluoromethoxy)phenyl)-1H-imidazo[4,5-c]pyridin-4(5H)-one;followed by Suzuki-couling with1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole,catalyzed by Pd-118/K₃PO₄ in dioxane/H₂O mixture under reflux conditionto provide the final product. ¹H NMR (DMSO-d₆, 300 MHz): δ 7.56 (s, 1H),7.51-7.45 (m, 3H), 7.31 (d, J=8.3 Hz, 2H), 6.99 (s, 1H), 3.99 (s, 3H),3.44 (s, 3H), 2.55 (s, 3H). MS (ESI) m/z (M+H)⁺ 404.1.

Compound 675 was prepared following the similar procedure for thesynthesis of Compound 674 using tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylatein place of1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. ¹HNMR (DMSO-d₆, 400 MHz) δ 13.07 (brs, 1H), 7.98 (brs, 1H), 7.69 (brs,1H), 7.59 (d, J=8.0 Hz, 2H), 7.50 (d, J=8.0 Hz, 2H), 7.21 (s, 1H), 3.40(s, 3H), 2.45 (s, 3H). MS (ESI) m/z (M+H)⁺ 390.0.

XV-4a was obtained in two steps from XV-2 following the similarprocedure described in the synthesis of XIV-7b and XIV-8b. XV-5a wasobtained by Suzuki-Coupling of XV-4a and XV-7 using the standardprocedure described herein.

Compound 569 was obtained by Suzuki-Coupling of XV-5a and XV-6afollowing the similar procedure described in the synthesis of Compound209. ¹H NMR (CDCl₃, 300 MHz) δ 7.83 (s, 1H), 7.79 (s, 1H), 7.52-7.47 (m,3H), 7.40 (d, J=8.7 Hz, 2H), 4.01 (s, 3H), 2.73 (s, 3H).

To a solution of XV-5a (150 mg, 0.39 mol) in MeOH (10 mL) was added Pd/C(20 mg), the mixture was stirred at rt under H₂ overnight. Aftercompletion of the reaction indicated by TLC (EA:PE=1:1), the mixture wasfiltered, the filtrate was concentrated in vacuo to afford a mixture ofCompound 570 and XV-5b. The mixture were added into CH₃C(OEt)₃ (10 mL).The mixture was heated at reflux overnight. After cooling to rt, themixture was filtered, the cake was collected and purified by prep-TLC(EA:PE=1:1) to give Compound 570 (50 mg, 41% yield). ¹H NMR (DMSO-d₆,300 MHz) δ 7.77 (d, J=7.5 Hz, 1H), 7.60-7.52 (m, 4H), 6.94 (d, J=7.2 Hz,1H), 2.59 (s, 3H).

Example 5-I Synthesis of Compounds 60-63 (Scheme XVI)

XVI-3 was prepared following the similar procedure for obtaining XIII-7.MS (ESI) m/z (M+H)⁺ 233.0.

XVI-4 was prepared following the similar procedure for obtaining XV-12,using ethyl iodide in place of methyl iodide. MS (ESI) m/z (M+H)⁺ 261.1.

XVI-5: A flask was charged with XVI-4 (150 mg, 0.57 mmol, 1 eq.),Pd₂(dba)₃ (285 mg, 0.46 mmol, 0.8 eq.), KOH (383 mg, 6.84 mmol, 12 eq.),Ligand (252 mg, 0.57 mmol, 1 eq.), 10 mL of dioxane and 10 mL of H₂O,flushed with nitrogen for three times. The mixture was heated at 100° C.for 10 hrs. LCMS analysis showed the reaction completed. The mixture wascooled down to rt, diluted with water, extracted with ethyl acetate (50mL×3). The combined organic layer was washed with brine, dried overanhydrous sodium sulfate, filtrated and concentrated. Purification byprep-TLC gave XVI-5 (130 mg, yield 72%). MS (ESI) m/z (M+H)⁺ 243.1.

Compound 60 was prepared following the similar procedure for obtainingX-6. ¹H NMR (CDCl₃, 400 MHz) δ 7.71 (s, 1H), 7.60 (s, 1H), 7.50 (d,J=8.4 Hz, 2H), 7.34 (d, J=8.4 Hz, 2H), 7.18 (d, J=2.8 Hz, 1H), 7.04 (s,1H), 6.47 (d, J=2.8 Hz, 1H), 4.61 (q, J=7.2 Hz, 2H), 3.97 (s, 3H), 1.48(t, J=7.2 Hz, 3H). MS (ESI) m/z (M+H)⁺ 403.1.

Compound 61 was prepared following the similar procedure for obtainingXII-7 using (4-ethoxy-2-methylphenyl)boronic acid in place of XII-6. ¹HNMR (CDCl₃, 300 MHz) δ 9.03 (d, J=2.0 Hz, 1H), 8.86 (d, J=2.0 Hz, 1H),7.73 (s, 1H), 7.16 (d, J=8.0 Hz, 1H), 6.89-6.84 (m, 2H), 4.07 (q, J=7.2Hz, 2H), 2.18 (s, 3H), 1.44 (t, J=7.2 Hz, 3H). MS (ESI) m/z (M+H)⁺359.9.

Compound 62 was prepared from Compound 61 following the similarprocedure for obtaining Compound 46. ¹H NMR (CDCl₃, 400 MHz) δ 8.93 (d,J=2.0 Hz, 1H), 8.90 (d, J=2.0 Hz, 1H), 7.57-7.54 (m, 2H), 7.43 (s, 1H),7.22-7.14 (m, 3H), 6.90-6.84 (m, 2H), 4.07 (q, J=7.2 Hz, 2H), 2.22 (s,3H), 1.44 (t, J=7.2 Hz, 3H). MS (ESI) m/z (M+H)⁺ 376.0.

Compound 63 was prepared from Compound 61 following the similarprocedure for obtaining Compound 47. ¹H NMR (CDCl₃, 400 MHz) δ 8.93 (d,J=2.0 Hz, 1H), 8.90 (d, J=2.0 Hz, 1H), 8.14 (s, 1H), 7.79 (s, 1H), 7.56(s, 1H), 7.20 (d, J=8.8 Hz, 1H), 6.90-6.85 (m, 2H), 4.08 (q, J=7.2 Hz,2H), 3.99 (s, 3H), 2.19 (s, 3H), 1.45 (t, J=7.2 Hz, 3H). MS (ESI) m/z(M+H)⁺362.0.

Example 5-J Synthesis of Compounds 582-584 and 586-587

A flask was charged with compound 1 (3.0 g, 1 eq.), malonic acid (1.2eq.), pyridine (20 mL), peperidine (1.56 mL). The mixture was stirredunder nitrogen atmosphere at 90° C. for 2 h, cooled, concentrated underreduced pressure, the residue was diluted with water and adjusted pH=˜5by adding aq. HCl, the resulting solid was filtered and washed withwater, the solid was dried in vacuo to give compound 2.

ClCOOEt (1.2 eq) was added into the solution of compound 2 (1.0 g, 1.0eq.) and TEA (1.3 eq) in 20 mL of acetone by dropwise at 0° C. Themixture was stirred at 0° C. for 1 h. The resulting mixture was addedinto the solution of sodium azide (4 eq.) in 30 mL of acetone and water(v/v=1:1) at 0° C. and stirred for 30 mins. The mixture was diluted withwater, extracted with EtOAc. The combined organic layer was washed withbrine, dried over anhydrous sodium sulfate, filtered and concentrated toafford compound 3.

Compound 3 was added into 10 mL of oxydibenzene. The mixture was stirredat 240° C. for 2 h, cooled the mixture to rt and stirred overnight,filtered the resulting brown solid and washed with EtOAc to givecompound 4 as a pale-brown solid.

A suspension of 4 (1 eq.), N-bromosuccinimide (1.1 eq.) and 50 mL of DMFwas stirred at rt for 4 h. The mixture was filtered; the solids werewashed successively with small amounts of DCM and dried to give compound5 as a brown solid.

Compound 7 was prepared from reacting compound 5 with compound 6 usingMethod 1 as described herein.

Compound 9 was prepared by Suzuki-coupling of Compound 7 with thecorresponding boronic ester 8 using the standard procedure A or Bdescribed herein.

Compound 582 was prepared following procedure A. ¹H NMR (DMSO-d₆, 300MHz) δ 12.96 (s, 1H), 9.73 (s, 1H), 8.42 (s, 1H), 8.18 (s, 1H), 8.13 (s,1H), 7.73 (d, J=8.7 Hz, 2H), 7.58 (d, J=8.7 Hz, 2H). MS (ESI) m/z (M+H)⁺378.9.

Compound 583 was prepared following procedure A. ¹H NMR (DMSO-d₆, 400MHz) δ 9.72 (s, 1H), 8.40 (s, 1H), 8.10 (d, J=9.6 Hz, 2H), 7.72 (d,J=8.8 Hz, 2H), 7.58 (d, J=8.4 Hz, 2H), 3.89 (s, 3H). MS (ESI) m/z (M+H)⁺393.0.

Compound 584 was prepared following procedure B. ¹H NMR (CDCl₃, 400 MHz)δ 8.18 (s, 1H), 7.80 (s, 1H), 7.52 (d, J=9.2 Hz, 3H), 7.38 (d, J=8.4 Hz,2H), 3.98 (s, 3H), 2.91 (s, 3H). MS (ESI) m/z (M+H)⁺ 407.0.

Compound 586 was prepared following procedure A. ¹H NMR (DMSO-d₆, 400MHz) δ 8.51 (s, 1H), 8.15 (s, 1H), 8.10 (s, 1H), 7.70 (d, J=8.8 Hz, 2H),7.57 (d, J=8.4 Hz, 2H), 7.35-7.24 (m, 5H), 5.39 (s, 2H), 2.90 (s, 3H).MS (ESI) m/z (M+H)⁺ 483.0.

Compound 587 was prepared following procedure B. ¹H NMR (DMSO-d₆, 300MHz) δ 12.94 (s, 1H), 8.41 (s, 1H), 8.16 (s, 1H), 8.08 (s, 1H), 7.71 (d,J=8.7 Hz, 2H), 7.58 (d, J=8.7 Hz, 2H), 2.91 (s, 3H). MS (ESI) m/z (M+H)⁺392.7.

Compound 585 was prepared by Suzuki-Coupling of2-methylthiazolo[5,4-c]pyridin-4(5H)-one with(4-(trifluoromethoxy)phenyl)boronic acid using the same method describedin the synthesis of Compound 7. ¹H NMR (DMSO-d₆, 400 MHz) δ 7.76 (d,J=7.2 Hz, 1H), 7.65 (d, J=9.2 Hz, 2H), 7.55 (d, J=8.8 Hz, 2H), 6.96 (d,J=7.2 Hz, 1H), 2.84 (s, 3H). MS (ESI) m/z (M+H)⁺ 326.8.

Example 5-K Synthesis of Compound 589

To a solution of compound 1 (5 g, 36 mmol) in THF (50 mL) was addedn-BuLi (2.5 M in hexane, 31.5 mL, 79 mmol) at −78° C., then the mixturewas stirred at 0° C. for 1 h. DMF (12 mL, 157.5 mmol) was added at −78°C., and then the mixture was stirred at 0° C. for additional 1 h. Aftercompletion of the reaction, the mixture was quenched with saturated aq.NH₄Cl. The mixture was concentrated in vacuo, the residue waspartitioned between H₂O and EtOAc. The organic layer was washed withbrine, dried over Na₂SO₄, concentrated in vacuo. The crude residue waspurified by column chromatography on silica gel (PE:EA=4:1) to affordcompound 2 (1.5 g, 25% yield).

To a solution of compound 2 (1.5 g, 9.0 mmol) in HCOOH (20 mL) was addedH₂O₂ (3.1 g, 27 mmol) at 0-4° C. The mixture was stirred at rtovernight. After completion of the reaction, the mixture was quenchedwith aq. NaHSO₃. The mixture was concentrated in vacuo, the residue waspartitioned between H₂O and EtOAc. The organic layer was washed withbrine, dried over Na₂SO₄, concentrated in vacuo. The crude residue waspurified by column chromatography on silica gel (PE:EA=1:1) to affordcompound 3 (1.5 g, 94% yield).

To a solution of compound 3 (1.5 g, 8.2 mmol) in toluene (20 mL) wasadded Et₃N (2.1 g, 20.5 mmol), 4 Å molecular sieve (3.0 g). The mixturewas purged with nitrogen for three times and then heated to reflux undernitrogen for 0.5 h. Then t-BuOH (0.73 g, 9.8 mmol), DPPA (2.4 g, 8.6mmol) were added in turn. The mixture was stirred at reflux overnight.After cooling to rt, the mixture was filtered, the filtrate waspartitioned between H₂O and EtOAc. The organic layer was washed withbrine, dried over Na₂SO₄, concentrated in vacuo. The crude residue waspurified by column chromatography on silica gel (PE:EA=3:1) to affordcompound 4 (500 mg, 42% yield).

Compound 6 was prepared by bromination of compound 4 using NBS followedby HBr hydrolysis. A mixture of compound 6 (300 g, 1.5 mmol) inCH₃C(OEt)₃ (10 mL) was refluxed overnight. After cooling to rt, themixture was filtered, the cake was washed with EA/PE (v/v=1/1) to givecompound 7 (150 mg, 44% yield). MS (ESI) m/z (M+H)⁺ 230.8.

Compound 589 was prepared from compound 7 by two Suzuki coupling stepsas indicated in the scheme above. ¹H NMR (DMSO-d₆, 300 MHz) δ 8.32 (s,1H), 8.05 (d, J=4.5 Hz, 2H), 7.68 (d, J=8.7 Hz, 2H), 7.59 (d, J=8.7 Hz,2H), 3.88 (s, 3H), 2.71 (s, 3H).

Preparation of Compound 588

The mixture of compound 1a (16 g, 60.4 mmol, 1 eq.), BnNHNH₂ (15 g,129.3 mmol, 2 eq.) in 100 mL of i-PrOH was sealed and heated bymicrowave at 110° C. for 20 min. TLC analysis (PE/EA=5/1) showed thereaction completed. The mixture was cooled to rt. The precipitate wasfiltered and washed with cool i-PrOH to give a light yellow solidCompound 2a. (16.5 g, 74% yield).

Compound 2a (12 g, 32.5 mmol, 1 eq.) was dissolved in 1200 mL of THF,treated with NaH (60% dispersion in mineral oil, 1.56 g, 39.02 mmol, 1.2eq.). The mixture was heated to reflux for 2 h. The mixture was cooleddown to rt. The reaction was quenched with water slowly, extracted withEtOAc. The combined organic layer was washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated to give brown oil.Purification by column (PE/EA=20/1-5/1) gave compound 3a (5.5 g, yield59%).

To a solution of compound 3a (5.5 g, 19.1 mmol, 1 eq.) in 100 mL of DCMwas added m-CPBA (6.5 g, 38.2 mmol, 2 eq.). The mixture was stirred for18 h at rt. The reaction was diluted with water, extracted with DCM. Thecombined organic layer was washed with brine, dried over anhydroussodium sulfate, filtered and concentrated to give brown oil.Purification by column (PE/EA=5/1-1/1) gave compound 4a (5.2 g, yield89%).

The solution of compound 4a (4 g, 13.1 mmol, 1 eq.) in 70 mL of Ac₂O washeated to reflux for 18 h. All the volatiles were removed under vacuo.The residue was diluted with MeOH and adjusted pH=7-8 with Et₃N. Themixture was stirred for 4 h at rt. The reaction was diluted with water,extracted with EtOAc (150 mL×3). The combined organic layer was washedwith brine, dried over anhydrous sodium sulfate, filtered andconcentrated to give brown oil. Purification by column chrom(PE/EA=5/1-1/1) gave compound 5a (0.6 g, yield 15%). MS (ESI) m/z(M+H)⁺305.9.

Compound 588 was prepared from compound 5a in three steps by Suzukicoupling with compound 8 followed by Suzuki coupling with compound 10,then deprotection of the benzyl group using KOt-Bu in DMSO. ¹H NMR(DMSO-d₆, 400 MHz) δ 14.37 (s, 1H), 8.33 (s, 1H), 8.28 (s, 1H), 7.94 (s,1H), 7.68 (d, J=8.4 Hz, 2H), 7.57-7.51 (m, 3H), 3.88 (s, 3H).

HCl salt Compound 588a: ¹H NMR (DMSO-d₆, 400 MHz) δ 8.38 (s, 1H), 8.28(s, 1H), 7.94 (s, 1H), 7.69 (d, J=8.8 Hz, 2H), 7.57 (d, J=8.8 Hz, 2H),7.50 (s, 1H), 3.88 (s, 3H). MS (ESI) m/z (M+H)⁺ 376.0.

Compounds 657 and 658 were prepared by reacting Compound 588 with ethyliodide and NaH in DMF. Compound 657: ¹H NMR (DMSO-d₆, 400 MHz): δ 8.62(s, 1H), 8.18 (s, 1H), 7.90 (s, 1H), 7.64 (d, J=8.8 Hz, 2H), 7.55 (d,J=8.8 Hz, 2H), 7.42 (s, 1H), 4.44 (q, J=7.2 Hz, 2H), 3.88 (s, 3H), 1.53(t, J=7.2 Hz, 3H). Compound 658: ¹H NMR (DMSO-d₆, 400 MHz): δ 8.27 (s,1H), 8.26 (s, 1H), 7.92 (s, 1H), 7.68 (d, J=8.8 Hz, 2H), 7.55 (d, J=8.8Hz, 2H), 7.51 (s, 1H), 4.72 (q, J=6.8 Hz, 2H), 3.88 (s, 3H), 1.40 (t,J=6.8 Hz, 3H).

Preparation of Compound 660

To a solution of compound 9a (1.8 g, 3.88 mmol, 1 eq.) in dioxane/H₂O(72 mL, v/v=5/1) was added K₃PO₄ (1.6 g, 7.76 mmol, 2 eq.), compound 10b(1.47 g, 4.66 mmol, 1.2 eq.), Pd-118 (125 mg, 0.19 mmol, 0.05 eq.). Themixture was purged with nitrogen and then heated at 95° C. for 8 hrs.The mixture was cooled to rt, diluted with water, extracted with EtOAc.The combined organic layer was washed with brine, dried over anhydrousNa₂SO₄, and concentrated in vacuo. The residue was purified by columnchromatography (PE/EA=1/1) to give 11a as white solid (1.3 g, 59%yield).

To a solution of compound 11a (1.3 g, 2.27 mmol, 1 eq.), DMSO (1.77 g,22.76 mmol, 10 eq.) in THF (75 mL) was added t-BuOK (5.1 g, 45.4 mmol,20 eq.) at 0° C. The mixture was stirred under oxygen atmosphere at rtfor 3 h. The reaction was quenched with water, extracted with EtOAc. Thecombined organic layer was washed with brine, dried over anhydrousNa₂SO₄, and concentrated in vacuo. The residue was purified by columnchromatography (PE/EA=1/3) to give crude compound 12a (1.1 g, 100%yield).

The solution of compound 12a (320 mg, 0.66 mmol, 1 eq.) in TFA (5 mL)was heated at 105° C. for 3 hrs. The mixture was cooled to rt. All thevolatiles were removed under reduced pressure. The residue wasneutralized with saturated aq. NaHCO₃, extracted with EtOAc. Thecombined organic layer was washed with brine, dried over anhydrousNa₂SO₄, and concentrated to give brown oil. Purification by columnchromatography gave Compound 660 (180 mg, 75% yield). ¹H NMR (DMSO-d₆,400 MHz): δ 14.27 (brs, 1H), 13.00 (brs, 1H), 8.38 (brs, 1H), 8.25 (brs,1H), 8.01 (brs, 1H), 7.67 (d, J=8.4 Hz, 2H), 7.55 (d, J=8.4 Hz, 2H),7.50 (s, 1H). MS (ESI) m/z (M+Na)⁺ 383.9.

Compounds 659 and 661 were prepared by reacting compound 12a with ethyliodide and NaH in DMF, separating the two intermediates and thentreating each with TFA to afforded the final products. Compound 659: ¹HNMR (DMSO-d₆, 400 MHz): δ 13.01 (brs, 1H), 8.65 (s, 1H), 8.09 (brs, 2H),7.63 (d, J=8.0 Hz, 2H), 7.53 (d, J=8.0 Hz, 2H), 7.43 (s, 1H), 4.43 (q,J=7.2 Hz, 2H), 1.51 (t, J=7.2 Hz, 3H). MS (ESI) m/z (M+H)⁺ 389.9.Compound 661: ¹H NMR (DMSO-d₆, 400 MHz): δ 13.04 (br, 1H), 8.30 (s, 1H),8.27-8.14 (br, 2H), 7.68 (d, J=8.4 Hz, 2H), 7.55 (d, J=8.4 Hz, 2H), 7.53(s, 1H), 4.72 (q, J=7.2 Hz, 2H), 1.40 (t, J=7.2 Hz, 3H). MS (ESI) m/z(M+H)⁺389.9.

Compound 689 was prepared by reacting compound 9a with(4-fluorophenyl)boronic acid catalyzed by Pd-118/K₃PO₄ in dioxane/H₂O at90° C., followed by t-BuOK deprotecting benzyl group to afford the finalproduct. ¹H NMR (CDCl₃, 400 MHz) δ 8.08 (s, 1H), 7.59-7.52 (m, 4H), 7.39(d, J=8.4 Hz, 2H), 7.19 (t, J=8.4 Hz, 2H), 7.08 (s, 1H). MS (ESI) m/z[M+H]⁺ 390.0.

Example 5-L Synthesis of Compound 617

To a solution of compound 1 (10 g, 37.8 mmol) was added 20 mL of HCOOH.The mixture was refluxed overnight. The mixture was concentrated,purified by column chromatography on silica gel (DCM: MeOH=5:1) to givecompound 2 (8 g, yield 99%).

A mixture of compound 2 (8.0 g, 37.4 mmol) in POCl₃ (10 mL) was refluxedfor 3 h. Cooled down to rt. Then poured into water slowly, adjustedpH=7-8 with saturated aq. NaHCO₃, extracted with EtOAc. The combinedorganic layer was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated. The residue was purified by column chromatography onsilica gel (PE:EA=2:1 to 1:1) to give compound 3 (4.57 g, 53% yield).

Compounds 4-8 were prepared following the similar procedures describedin Example 5-F.

Compound 617 was prepared by Suzuki-Coupling of compound 8 with compound9 following the standard procedure described herein as a white solid.

Alternative Synthesis of Compound 617

The detailed synthetic procedure for the alternative synthesis ofCompound 617 has been described herein. ¹H NMR (DMSO-d₆, 400 MHz) δ 8.41(s, 1H), 8.36 (s, 1H), 8.06 (s, 1H), 7.78 (s, 1H), 7.65 (d, J=8.8 Hz,2H), 7.54 (d, J=8.8 Hz, 2H), 4.45 (q, J=7.2 Hz, 2H), 3.86 (s, 3H), 1.40(t, J=7.2 Hz, 3H).

Compound 618 was prepared by Suzuki-Coupling of compound 6 with compound9, followed by HBr acid hydrolysis. ¹H NMR (CDCl₃, 400 MHz) δ 8.20 (d,J.=6.4 Hz, 1H), 7.93 (s, 1H), 7.38 (s, 1H), 4.56 (d, J.=7.2 Hz, 2H),3.95 (s, 3H), 1.53 (t, J.=7.2 Hz, 3H). MS (ESI) m/z (M+H)⁺ 244.1.

Example 5-M Synthesis of Compound 619

A solution of NaNO₂ (7.8 g, 113.3 mmol) in water (30 mL) was addeddropwise into a solution of compound 1 (20 g, 75.5 mmol) in 2Nhydrochloric acid (100 mL) at 0° C., and stirred for 1 h at 0° C. Theprecipitate was filtered and wash with ice-water and dried in vacuum toafford compound 2 (17 g, 82% yield) as a yellow brown solid.

Compounds 3, 4A-4C, 5A, and 7A were prepared following the similarprocedures described in Example 5-F.

Compound 619 was prepared by Suzuki-Coupling of compound 7a withcompound 8 following the standard procedure described herein. ¹H NMR(CDCl₃, 400 MHz) δ 8.08 (s, 1H), 7.84 (s, 1H), 7.52 (d, J=8.0 Hz, 2H),7.38 (d, J=8.4 Hz, 3H), 4.78 (q, J=6.8 Hz, 2H), 3.99 (s, 3H), 1.74 (t,J=6.8 Hz, 3H).

Compound 620 was prepared following the similar procedure described inthe synthesis of Compound 619 using the Boc-protected boronic ester inplace of compound 8. ¹H NMR (CDCl₃, 400 MHz) δ 12.99 (s, 1H), 8.34 (s,1H), 8.15 (s, 1H), 7.96 (s, 1H), 7.65-7.69 (m, 2H), 7.57 (d, J=8.4 Hz,2H), 4.79 (q, J=7.2 Hz, 2H), 1.63 (t, J=7.2 Hz, 3H).

Compound 624 was prepared from compound 4B following the generalprocedure described above. ¹HNMR (DMSO-d₆, 400 MHz) δ 8.01 (s, 1H), 7.71(s, 1H), 7.67-7.65 (m, 2H), 7.55-7.53 (m, 3H), 4.42 (q, J=7.2 Hz, 2H),3.90 (s, 3H), 1.20 (t, J=7.2 Hz, 3H). MS (ESI) m/z [M+H]⁺ 405.1.

Compound 633 was prepared from compound 4B following the generalprocedure described above to form an intermediate compound 7B followedby Pd/C hydrogenation to afforded the final product. ¹HNMR (CDCl₃, 400MHz) δ 7.46 (d, J=8.8 Hz, 2H), 7.37-7.33 (m, 3H), 6.50 (d, J=7.2 Hz,1H), 4.60 (q, J=7.2 Hz, 2H), 1.64 (t, J=7.2 Hz, 3H). MS (ESI) m/z [M+H]⁺324.9.

Compound 625 was prepared from compound 4C following the generalprocedure described above. ¹H NMR (DMSO-d₆, 400 MHz) δ 8.47 (s, 1H),8.13 (s, 1H), 7.90 (s, 1H), 7.71-7.69 (m, 2H), 7.59 (d, J=8.4 Hz, 2H),4.86 (q, J=7.2 Hz, 2H), 3.91 (s, 3H), 1.52 (t, J=7.2 Hz, 3H). MS (ESI)m/z [M+H]⁺ 405.1.

Compound 630 was prepared from compound 4C following the generalprocedure described above to form an intermediate compound 7C followedby Pd/C hydrogenation to afforded the final product. ¹HNMR (CDCl₃, 400MHz) δ 7.46 (d, J=8.8 Hz, 2H), 7.38 (d, J=8.8 Hz, 2H), 7.19 (d, J=7.2Hz, 1H), 6.93 (d, J=7.2 Hz, 1H), 4.92 (q, J=7.2 Hz, 2H), 1.63 (t, J=7.2Hz, 3H). MS (ESI) m/z [M+H]⁺ 325.1.

Compound 634 was prepared by Suzuki-Coupling of compound 7C withtert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylateusing Pd-118, K₃PO₄ in dioxane/H₂O. ¹HNMR (DMSO-d₆, 400 MHz) δ 13.1 (s,1H), 8.47 (s, 1H), 8.23 (s, 1H), 7.93 (s, 1H), 7.71 (d, J=8.8 Hz, 2H),7.59 (d, J=8.8 Hz, 2H), 4.86 (q, J=7.2 Hz, 2H), 1.53 (t, J=7.2 Hz, 3H).MS (ESI) m/z [M+H]⁺ 391.1.

HCl salt compound 634a: ¹HNMR (DMSO-d₆, 400 MHz) δ 8.36 (s, 2H), 7.93(s, 1H), 7.70 (d, J=8.4 Hz, 2H), 7.59 (d, J=8.4 Hz, 2H), 4.86 (q, J=7.2Hz, 2H), 1.53 (t, J=7.2 Hz, 3H). MS (ESI) m/z [M+H]₊391.0.

Compound 621 was prepared by Suzuki-Coupling of compound 4C withcompound 8 followed by HBr hydrolysis. ¹H NMR (DMSO-d₆, 400 MHz) δ 11.8(s, 1H), 8.39 (s, 1H), 8.08 (s, 1H), 7.50 (s, 1H), 4.85 (q, J=7.2 Hz,2H), 3.91 (s, 3H), 1.52 (t, J=7.2 Hz, 3H).

Compound 622 was prepared by Suzuki-Coupling of compound 4B withcompound 8 followed by HBr hydrolysis. ¹H NMR (DMSO-d₆, 400 MHz) δ 11.66(s, 1H), 7.96 (s, 1H), 7.64 (s, 1H), 7.13 (s, 1H), 4.31 (q, J=7.2 Hz,2H), 3.90 (s, 3H), 1.15 (t, J=7.2 Hz, 3H).

Compound 623 was prepared by amino protection of compound 3 using SEMCland NaH in DMF, followed by Suzuki-Coupling with compound 8 then HClhydrolysis in MeOH as a white solid. ¹H NMR (DMSO-d₆, 400 MHz) δ 11.61(s, 1H), 8.28 (s, 1H), 7.99 (s, 1H), 7.47 (s, 1H), 3.89 (s, 3H). MS(ESI) m/z (M+H)⁺ 216.9.

Compound 631 was prepared from Compound 623 by first protecting thetriazole hydrogen with Trt-Cl, then Suzuki-Coupling with(4-(trifluoromethoxy)phenyl)boronic acid using standard proceduredescribed herein, followed by deprotecting in HCl/MeOH solution. ¹HNMR(DMSO-d₆, 400 MHz) δ 8.38 (s, 1H), 8.07 (s, 1H), 7.89 (s, 1H), 7.69 (d,J=8.4 Hz, 2H), 7.58 (d, J=8.4 Hz, 2H), 3.90 (s, 3H). MS (ESI) m/z [M+H]⁺376.9.

Compound 632 was prepared by reacting3-benzyl-7-bromo-3H-[1,2,3]triazolo[4,5-c]pyridin-4(5H)-one withcompound 6, followed by deprotection of the Bz group using Pd/C inhydrogen atmosphere (45 Psi) at rt overnight. ¹H NMR (CDCl₃, 400 MHz) δ7.67-7.60 (m, 3H), 7.55 (d, J=8.8 Hz, 2H), 6.82 (brs, 1H). MS (ESI) m/z(M+H)⁺ 296.9.

Compound 635 was prepared following the similar synthetic schemedescribed in the synthesis of Compound 619 using isopropyl iodide inplace of ethyl iodide in the reaction with compound 3. ¹H NMR (CDCl₃,400 MHz) δ 8.08 (s, 1H), 7.85 (s, 1H), 7.51 (d, J=8.8 Hz, 2H), 7.37 (d,J=8.8 Hz, 2H), 7.36 (s, 1H), 5.19-5.12 (m, 1H), 4.00 (s, 3H), 1.75 (d,J=6.8 Hz, 6H).

Compound 676 was prepared following the similar procedure described inthe synthesis of Compound 619. First,7-bromo-3-isopropyl-4-methoxy-3H-[1,2,3]triazolo[4,5-c]pyridine wasformed by reacting compound 3 with isopropyl iodide; followed byPd(dppf)Cl₂ catalyzed Suzuki-coupling with compound 8, subsequent acidhydrolysis to form1-isopropyl-7-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-c]pyridin-4(5H)-one.Finally, copper acetate catalyzed coupling with compound 6 provided thefinal product. ¹H NMR (CDCl₃, 400 MHz) δ 8.41 (s, 1H), 7.85 (s, 1H),7.52 (d, J=8.4 Hz, 2H), 7.41 (d, J=8.4 Hz, 2H), 7.37 (s, 1H), 5.73-5.66(m, 1H), 4.00 (s, 3H), 1.75 (d, J=6.8 Hz, 6H). MS (ESI) m/z (M+H)⁺418.9.

Compound 677 was prepared similarly as Compound 676 using7-bromo-1-isopropyl-4-methoxy-3H-[1,2,3]triazolo[4,5-c]pyridine asstarting material. ¹H NMR (CDCl3, 400 MHz) δ 7.59 (s, 1H), 7.54 (s, 1H),7.48 (d, J=8.4 Hz, 2H), 7.34 (d, J=8.4 Hz, 2H), 7.13 (s, 1H), 4.67-4.57(m, 1H), 4.01 (s, 3H), 1.55 (d, J=6.8 Hz, 6H). MS (ESI) m/z (M+H)⁺418.8.

Compound 679 was prepared following the similar procedure described inthe synthesis of Compound 676 using7-bromo-2-(2-fluoroethyl)-4-methoxy-2H-[1,2,3]triazolo[4,5-c]pyridine asstarting material as a white solid. ¹H NMR (DMSO-d₆, 400 MHz) δ 8.31 (s,1H), 8.07 (s, 1H), 7.93 (s, 1H), 7.68 (d, J=8.8 Hz, 2H), 7.58 (d, J=8.8Hz, 2H), 5.14 (s, 2H), 5.09-5.06 (m, 1H), 5.03-5.01 (m, 1H), 3.89 (s,3H).

Compound 684 was prepared following the similar procedure described inthe synthesis of Compound 676 using7-bromo-3-(2-fluoroethyl)-4-methoxy-2H-[1,2,3]triazolo[4,5-c]pyridine asstarting material. ¹H NMR (CDCl₃, 400 MHz) δ 8.47 (s, 1H), 7.87 (s, 1H),7.52 (d, J=8.8 Hz, 2H), 7.43-7.39 (m, 3H), 5.27 (t, J=4.8 Hz, 1H), 5.22(t, J=4.8 Hz, 1H), 5.04 (t, J=4.8 Hz, 1H), 4.92 (t, J=4.8 Hz, 1H), 4.01(s, 3H).

Compound 687 was prepared following the similar procedure described inthe synthesis of Compound 676 using7-bromo-1-(2-fluoroethyl)-4-methoxy-2H-[1,2,3]triazolo[4,5-c]pyridine asstarting material. ¹H NMR (CDCl₃, 400 MHz) δ 7.60 (s, 1H), 7.54 (s, 1H),7.50 (d, J=8.8 Hz, 2H), 7.36 (d, J=8.8 Hz, 2H), 7.18 (s, 1H), 4.85 (t,J=4.8 Hz, 1H), 4.73 (t, J=4.8 Hz, 1H), 4.65 (t, J=4.8 Hz, 1H), 4.60 (t,J=4.8 Hz, 1H), 4.01 (s, 3H).

A mixture of compound 4A (1.0 g, 3.906 mmol, 1 eq), compound 9 (820 mg,5.859 mmol, 1.5 eq), Pd(dppf)Cl₂ (287 mg, 0.391 mmol, 0.1 eq) and K₂CO₃(1.08 g, 7.812 mmol, 2 eq) in DME/H₂O (20 mL, v/v=5/1) was flushed withN₂. And then the mixture was stirred at 80° C. under N₂ for 1 h. 30 mLof water was added and extracted with EtOAc. The combined organic layerwas washed with brine, dried over Na₂SO₄ and concentrated. The residuewas purified to afford compound 10A (750 mg, 71% yield).

A mixture of compound 10A (650 mg, 2.39 mmol) in HCl/MeOH (4M, 50 mL)was stirred at 70° C. overnight. The mixture was concentrated andadjusted to pH=7-8 with saturated aq. NaHCO₃. The mixture was filteredand the filter cake was dried in vacuum to afford compound 11A (570 mg,92% yield).

A flask was charged with compound 11A (250 mg, 0.97 mmol, 1 eq),compound 6 (260 mg, 1.26 mmol, 1.3 eq), Cu(OAc)₂ (351 mg, 1.94 mmol, 2eq), Py (230 mg, 2.91 mmol, 3 eq), pyridine N-Oxide (184 mg, 1.94 mmol,2 eq) and 4 Å molecular sieves (150 mg) in DMF. The mixture was stirredunder O₂ at rt overnight. The mixture was concentrated and 50 mL ofwater was added. The mixture was extracted with EtOAc. The combinedorganic layer was washed with brine, dried over Na₂SO₄ and concentrated.The residue was purified to afford Compound 680 (300 mg, 74% yield) as awhite solid. ¹H NMR (DMSO-d₆, 400 MHz) δ 8.02 (dd, J=5.6, 8.8 Hz, 2H),7.89 (s, 1H), 7.71 (d, J=8.8 Hz, 2H), 7.57 (d, J=8.4 Hz, 2H), 7.31 (t,J=8.8 Hz, 2H), 4.78 (q, J=7.2 Hz, 2H), 1.59 (t, J=7.2 Hz, 3H). MS (ESI)m/z [M+H]⁺ 419.0.

Compound 682 was prepared following the similar procedure described inthe synthesis of Compound 680 using 4B as starting material. ¹H NMR(CDCl₃, 400 MHz) δ 7.53 (d, J=8.8 Hz, 2H), 7.43 (dd, J=3.2, 8.4 Hz, 2H),7.36 (d, J=8.4 Hz, 2H), 7.25-7.19 (m, 3H), 4.23 (q, J=7.2 Hz, 2H), 1.24(t, J=7.2 Hz, 3H).

Compound 683 was prepared following the similar procedure described inthe synthesis of Compound 680 using 4C as starting material. ¹H NMR(CDCl₃, 400 MHz) δ 7.93-7.90 (m, 2H), 7.53 (d, J=8.8 Hz, 2H), 7.42 (d,J=8.4 Hz, 2H), 7.34 (s, 1H), 7.19 (t, J=8.8 Hz, 2H), 4.99 (q, J=7.2 Hz,2H), 1.67 (t, J=7.2 Hz, 3H).

Compound 685 was prepared following the similar procedure described inthe synthesis of Compound 680 using 4-(tributylstannyl)pyridazine inplace of compound 9 catalyzed by Pd(PPh₃)₂Cl₂ in dioxane refluxedovernight. After HCl hydrolysis, (4-ethoxy-2-methylphenyl)boronic acidwas used in place of compound 6 to afford the final product. ¹H NMR(CDCl₃, 400 MHz) δ 9.70 (s, 1H), 9.22 (d, J=5.2 Hz, 1H), 8.12 (dd,J=2.4, 5.4 Hz, 1H), 7.68 (s, 1H), 7.18 (d, J=8.4 Hz, 1H), 6.91-6.83 (m,2H), 4.80 (q, J=7.4 Hz, 2H), 4.08 (q, J=6.8 Hz, 2H), 2.17 (s, 3H), 1.76(t, J=7.4 Hz, 3H), 1.45 (t, J=7.0 Hz, 3H).

Compound 686 was prepared following the similar procedure described inthe synthesis of Compound 619 using (4-ethoxy-2-methylphenyl)boronicacid in place of compound 6 to afford the final product. ¹H NMR (CDCl₃,400 MHz) δ 8.07 (s, 1H), 7.83 (s, 1H), 7.26 (s, 1H), 7.18 (d, J=8.8 Hz,1H), 6.88 (d, J=2.4 Hz, 1H), 6.85 (dd, J=2.4, 8.8 Hz, 1H), 4.77 (q,J=7.2 Hz, 2H), 4.08 (q, J=7.2 Hz, 2H), 3.99 (s, 3H), 2.16 (s, 3H), 1.75(t, J=7.2 Hz, 3H), 1.45 (t, J=7.2 Hz, 3H).

Compound 688 was prepared following the similar procedure described inthe synthesis of Compound 619 using (4-(2-methoxyethoxy)phenyl)boronicacid in place of compound 6 to afford the final product. ¹H NMR (CDCl₃,400 MHz) δ 8.07 (s, 1H), 7.84 (s, 1H), 7.39-7.34 (m, 3H), 7.06 (dd,J=2.0, 6.8 Hz, 2H), 4.77 (q, J=7.2 Hz, 2H), 4.19 (t, J=4.8 Hz, 2H), 3.99(s, 3H), 3.79 (t, J=4.8 Hz, 2H), 3.48 (s, 3H), 1.74 (t, J=7.2 Hz, 3H).

Example 5-N Synthesis of Compound 626

Hydrogen peroxide (30%, 35 mL) was added slowly to the solution ofcompound 1 (40 g, 186.8 mmol) in TFA (200 mL). The resulting mixture wasstirred at 70° C. for 2 h and at 90° C. for another 3 h. After themixture was cooled to rt, the mixture was poured over crushed ice. Themixture was extracted with DCM. The combined organic layers were washedwith aq. Na₂S₂O₃ and brine, dried over anhydrous Na₂SO₄, andconcentrated in vacuo to afford compound 2 (45 g, 96% crude yield),which was used directly for the next step.

Compound 2 (45 g, 180 mmol) was added to the mixture of conc. sulfuricacid (200 mL) and fuming nitric acid (150 mL) at rt during stirring. Themixture was heated to 100° C. and then stirred for 2 h. The reactionmixture was allowed to cool to rt and then poured over crushed ice. Themixture was neutralized with NH₃.H₂O in the ice bath. The precipitatewas filtered and washed with PE to give compound 3 (29.6 g, 56% yield).

Compound 3 (18 g, 60.84 mmol) was added into the stirring PBr₃ (46 mL)in portions at 0-5° C. The mixture was stirred at 5° C. for about 7 h,and then it was poured over crushed ice and extracted with EA. Thecombined organic layers were washed with brine, dried over anhydrousNa₂SO₄, and concentrated in vacuo to afford the crude product, which waspurified by flash column chromatography (PE:EA=10:1) to give compound 4(10 g, 59% yield).

Compounds 5-10 were prepared following the general procedure describedin the synthesis of Compound 48.

Compound 626 was prepared by Suzuki-Coupling of compounds 10 and 11. ¹HNMR (CDCl₃, 400 MHz) δ 7.51 (d, J=8.4 Hz, 2H), 7.44-7.41 (m, 2H), 7.32(d, J=8.4 Hz, 2H), 7.14 (t, J=8.4 Hz, 2H), 6.94 (d, J=2.8 Hz, 1H),6.91-6.89 (m, 2H), 3.67 (q, J=7.2 Hz, 2H), 1.10 (t, J=7.2 Hz, 3H). MS(ESI) m/z (M+H)⁺ 417.1.

Example 5-O Synthesis of Compound 656

Cs₂CO₃ (124 g, 0.38 mol) was added to a solution of the compound 1 (60g, 0.63 mol) in acetone (500 mL). And then iodoethane (118 g, 0.76 mol,61 mL) was added to the stirring mixture. The mixture was stirred atreflux overnight. The mixture was cooled to rt, filtered and the solventwas evaporated. The residue was purified by column chromatography(PE:EA=200:1 to 100:1) to afford compound 2(30 g, 39% yield).

A flask was charged with compound 2 (23 g, 187 mmol), malonic acid (23.3g, 224 mmol), pyridine (100 mL) and piperidine (22 mL). The mixture wasreflux under nitrogen atmosphere overnight. Then the mixture was cooledto rt and concentrated under reduced pressure. The residue was dilutedwith water and adjusted to pH=˜5 by aq. HCl (2 N), the resulting solidwas filtered and washed with amount water, the solid was dried in vacuoto give compound 3 (26.3 g, 85% yield).

Ethyl chloroformate (10 g, 87.6 mmol) was added dropwise into thesolution of compound 3 (10 g, 73 mmol) and TEA (11.1 g, 109.5 mmol) in100 mL of acetone at 0° C. The mixture was stirred at 0° C. for 1.5 h.The resulting mixture was added into the solution of sodium azide (14.3g, 219 mmol) in 30 mL of acetone and water (V/V=1/1) at 0° C. andstirred for 30 min. Then the mixture was warmed to rt and stirred foranother 2 h. The mixture was poured onto ice-water and the precipitatewas collect by filtration. The solid was washed with amount water, driedin vacuo to give compound 4 (2.87 g, 21% yield).

Compound 4 (2.8 g, 15 mmol) was added into 20 mL of diphenyl ether andthe mixture was stirred at 240° C. for 3 h. Then the mixture was cooledto rt and the residue was purified by column chromatography (PE:EA=1:1to EA:MeOH=100:1) to afford compound 5 (1.1 g, 46% yield).

To a solution of compound 5 (200 mg, 1.24 mmol) in DCM (10 mL) was addedcompound 6 (306.5 mg, 1.49 mmol), Cu(OAc)₂ (743 mg, 2.48 mmol), Pyridine(1.17 g, 12.4 mmol, 1.2 mL) and Pyridine-N-Oxide (295 mg, 3.1 mmol),followed by addition of 4 Å molecular sieve (100 mg). The reactionmixture was stirred at 30° C. under oxygen atmosphere overnight. Theresulting mixture was filtered and washed with EtOAc; the filtrate waswashed with brine, dried over Na₂SO₄ and concentrated in vacuo. Theresidue was purified by column chromatography on silica gel (PE/EA=1:1)to give Compound 656 (80 mg, 20% yield). ¹H NMR (CDCl₃, 400 MHz) δ 7.46(d, J=9.2 Hz, 2H), 7.32 (d, J=8.0 Hz, 2H), 7.10 (d, J=7.6 Hz, 1H), 6.93(d, J=3.2 Hz, 1H), 6.84 (d, J=3.2 Hz, 1H), 6.45 (d, J=7.2 Hz, 1H), 4.10(q, J=7.2 Hz, 2H), 1.48 (t, J=7.2 Hz, 3H). MS (ESI) m/z (M+H)⁺ 323.0.

To a solution of compound 656 (1.8 g, 5.6 mmol) in DMF′ (20 mL) wasadded NCS (1.53 g, 11.5 mmol). The mixture was heated at 90° C. for 2hrs. Then the mixture was washed with water, extracted with EA. Theorganic layer was washed with brine, dried under Na₂SO₄, concentrated invacuo. The crude residue was purified to afford compound 7 (1.6 g, 73%yield).

To a solution of compound 7 (1.0 g, 2.56 mmol) in MeCN (20 mL) was addedNBS (543 mg, 3.07 mmol) at 0-5° C. The mixture was stirred at rtovernight. Then the mixture was concentrated in vacuo. The crude residuewas purified to afford compound 8 (0.5 g, 42% yield).

To a stirred mixture of compound 8 (800 mg, 1.7 mmol), and 9 (530 mg,2.55 mmol) in dioxane/H₂O (30 mL, V:V=5:1) was added K₃PO₄ (720 mg, 3.4mmol), Pd(dppf)Cl₂ (125 mg, 0.17 mmol) under N₂ protection. The reactionmixture was heated at 90° C. overnight. The mixture was poured intowater, extracted with EtOAc, the organic layer was washed with brine,dried over anhydrous Na₂SO₄, and concentrated in vacuo, the residue waspurified to afford compound 10 (310 mg, yield: 38.8%).

Compound 10 (250 mg, 0.53 mmol) was dissolved in MeOH (20 mL), Pd/C (30mg) was added under N₂ protect, the reaction was stirred overnight at H₂balloon at 50° C. The suspension was filtered through a pad of celite.The filter cake was washed with MeOH, the combined filtrate wasconcentrated in vacuo, the crude product was purified to afford Compound694 (95 mg, 45% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.57 (s, 1H),7.49-7.42 (m, 3H), 7.29 (d, J=8.4 Hz, 2H), 6.93-6.90 (m, 1H), 6.89-6.84(m, 2H), 3.96 (s, 3H), 3.86 (q, J=7.2 Hz, 2H), 1.18 (t, J=7.2 Hz, 3H).MS (ESI) m/z [M+H]⁺ 403.1.

Compound 695 was prepared following the similar procedure described inthe synthesis of Compound 694 using1-benzyl-5-(4-(trifluoromethoxy)phenyl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-oneas starting material. ¹H NMR (DMSO-d₆, 400 MHz) δ 11.5 (s, 1H), 8.16 (s,1H), 7.83 (s, 1H), 7.61 (d, J=8.8 Hz, 2H), 7.51 (d, J=8.8 Hz, 2H), 7.42(s, 1H), 7.19 (s, 1H), 6.66 (s, 1H), 3.89 (s, 3H).

Example 5-P Synthesis of Compound 678

To a solution of BnOH (2.3 g, 21.7 mmol) in DMF (50 mL) was added NaH(60% dispersion in mineral oil, 1.5 g, 36.2 mmol) at 0° C., the mixturewas stirred for 30 mins at rt, compound 1 (5 g, 18.1 mmol) was added,the solution was heated to 100° C. for 3-4 hours, then quenched with aq.HCl (1N), extracted with EA, the combined organic layer was washed withbrine and concentrated to give crude product, which was purified toafford compound 2 (4 g, yield 72%).

To a solution of compound 2 (4 g, 13.2 mmol) in DMF (50 mL) was addedNaH (60% dispersion in mineral oil, 1 g, 26.4 mmol) at 0° C., themixture was stirred for 30 minutes at rt, and then SEM-Cl (3.3 g, 19.8mmol) was added, the reaction was stirred for 12 hours at rt. Themixture was quenched with water, extracted with EA, the combined organiclayer was washed with brine and concentrated to give crude product, theresidue was purified to afford compound 3 (3.7 g, yield 65%).

To a stirred mixture of compound 3 (4 g, 9.2 mmol), and 3A (4.2 g, 18.4mmol) in dioxane/H₂O (100 mL, V/V=5/1) was added K₃PO₄ (3.9 g, 18.4mmol), Pd-118 (600 mg, 0.92 mmol) under N₂ protection. The reactionmixture was heated to 60-70° C. overnight. The mixture was poured intowater, extracted with EtOAc, the organic layer was washed with brine,dried over anhydrous Na₂SO₄, and concentrated in vacuo, the residue waspurified by column chromatography on silica gel (PE/EA=5:1) to affordcompound 4 (3 g, yield 62.5%).

To a solution of compound 4 (3 g, 5.7 mmol) in MeOH (50 mL) was addedPd/C (600 mg) under N₂ protection, the reaction was stirred overnightunder H₂ balloon at rt, then the mixture was filtered through a pad ofcelite. The filter cake was washed with MeOH (50 mL), the combinedfiltrates was concentrated in vacuo, the crude product was purified toafford compound 5 (1.2 g, 48% yield).

To a solution of compound 5 (400 mg, 0.93 mmol) in DMF (20 mL) was addedcompound 5A (288 mg, 1.4 mmol), and Cu(OAc)₂ (336.7 mg, 1.86 mmol), Py(367.4 mg, 4.65 mmol), pyridine N-Oxide (176.7 mg, 1.86 mmol). Thereaction mixture was stirred at 50° C. overnight, and then it was pouredinto water, extracted with EA, the combined organic layer was washedwith brine and concentrated to give crude product. The residue waspurified to afford compound 6 (300 mg, yield 54%).

Compound 6 (700 mg, 1.18 mmol) was dissolved in HCl/MeOH (4M, 20 mL),the reaction was stirred for 1-2 hours at rt, and then the solvents wereevaporated. The residue was neutralized with saturated aq. NaHCO₃, andextracted with EA. The combined organic layer was concentrated in vacuo,and the crude product was washed with EA to afford Compound 678 (260 mg,61% yield). ¹H NMR (DMSO-d₆, 400 MHz) δ 8.28 (brs, 2H), 7.92 (s, 1H),7.69 (d, J=8.4 Hz, 2H), 7.57 (d, J=8.0 Hz, 2H). MS (ESI) m/z [M+H]⁺362.9.

Compound 681 was prepared following the similar procedure described inthe synthesis of Compound 678 using (4-fluorophenyl)boronic acid inplace of compound 3A. ¹H NMR (CD₃OD, 400 MHz) δ 7.84-7.80 (m, 2H),7.70-7.64 (m, 3H), 7.49 (d, J=8.4 Hz, 2H), 7.25-7.20 (m, 2H). MS (ESI)m/z [M+H]+ 391.0.

Example 6-A Synthesis of Compound 64 (Scheme XVII)

A mixture of XVII-1 (1.57 g, 8.35 mmol), XVII-2 (1.61 g, 9.19 mmol),Pd(OAc)₂ (0.187 g, 0.835 mmol), n-BuPAd₂ (0.298 g, 0.835 mmol) andCs₂CO₃ (8.17 g, 25.05 mmol) in toluene/H₂O (50 mL/10 mL) was degassed bypurging with nitrogen. The mixture was heated at 100° C. for 12 hrs.After being cooled to rt, the mixture was diluted with water (30 mL),extracted with EtOAc (100 mL×3). The combined organic layer was washedwith brine, dried over anhydrous Na₂SO₄, and concentrated in vacuo. Theresidue was purified by flash chromatography on silica gel(PE/EA=100:1→40:1) to produce XVII-3 as a yellow oil (0.8 g, 54% yield).

Compound 64: ¹H NMR (CDCl₃, 300 MHz) δ 7.50-7.47 (m, 2H), 7.42-7.34 (m,4H), 7.12 (d, J=2.1 Hz, 1H), 6.64 (d, J=6.9 Hz, 1H), 2.72-2.80 (m, 1H),2.05-1.96 (m, 2H), 1.80-1.63 (m, 4H), 1.52-1.47 (m, 2H). MS (ESI) m/z[M+H]⁺ 240.1.

Example 6-B Synthesis of Compound 65 (Scheme XVIII)

To a solution of XVIII-1 (2.1 g, 10.9 mmol) in toluene/H₂O (60 mL,v/v=5/1) was added Na₂CO₃ (1.4 g, 14.71 mmol), XVIII-2 (1.2 g, 11.99mmol), followed by Pd(dppf)Cl₂ (812 mg, 1.11 mmol). The mixture waspurged with nitrogen and then heated at reflux overnight. The mixturewas cooled to rt., diluted with water (50 mL), extracted with EtOAc (100mL×3). The combined organic layer was washed with brine, dried overanhydrous Na₂SO₄, and concentrated in vacuo. The residue was purified byflash chromatography on silica gel (PE/EA 100:1→40:1) to give XVIII-3 asa yellow oil (0.4 g, 24% yield). ¹H NMR (CDCl₃, 300 MHz) δ 7.97 (d,J=2.4 Hz, 1H), 7.46 (dd, J=8.4, 2.4 Hz, 1H), 6.68 (d, J=8.4 Hz, 1H),3.90 (s, 3H), 3.51-3.40 (m, 1H), 2.37-2.30 (m, 2H), 2.28-1.99 (m, 3H),1.96-1.82 (m, 1H).

Compound 65: ¹H NMR (CDCl₃, 400 MHz) δ 7.51-7.47 (m, 2H), 7.46-7.36 (m,4H), 7.08 (d, J=2.8 Hz, 1H), 6.65 (d, J=9.2 Hz, 1H), 3.35-3.26 (m, 1H),2.31-2.23 (m, 2H), 2.09-1.96 (m, 3H), 1.87-1.83 (m, 1H). MS (ESI) m/z[M+H]⁺ 226.0.

Compound 66 was prepared following the similar procedure for obtainingCompound 64. ¹H NMR (CDCl₃, 400 MHz) δ 7.51-7.46 (m, 2H), 7.43-7.33 (m,4H), 7.09 (d, J=2.4 Hz, 1H), 6.63 (d, J=9.6 Hz, 1H), 2.32-2.25 (m, 1H),1.87-1.82 (m, 4H), 1.76-1.72 (m, 1H), 1.41-1.18 (m, 5H). MS (ESI) m/z[M+H]⁺ 254.1.

Example 7 Synthesis of Compounds 67-76 (Scheme XIX)

XIX-3 was prepared following the similar procedure for obtaining V-3using XIX-2 in place of V-2 as a yellow solid.

XIX-5 was prepared following the similar procedure for obtainingCompound 23 using XIX-4 in place of V-4.

XIX-7: To a stirring solution of XIX-5 (1.0 eq) and TEA (3 eq.) in DCMwas added acyl chloride (2.0 eq) dropwise at 0° C. The mixture wasstirred for 1 h at rt. then it was washed with water and brine, driedover Na₂SO₄, and concentrated under reduced pressure. The residue waspurified by prep-TLC (EtOAc) to afford XIX-7.

Compound 67: ¹H NMR (CDCl₃, 400 MHz) δ 8.34 (s, 1H), 7.82 (s, 1H),7.59-7.41 (m, 7H), 6.77-6.74 (m, 1H), 2.72 (s, 3H).

Compound 68: ¹H NMR (CDCl₃, 400 MHz) δ 8.54 (s, 1H), 8.13 (d, J=7.2 Hz,2H), 7.91 (s, 1H), 7.66-7.43 (m, 10H), 6.78 (d, J=9.6 Hz, 1H).

Compound 69: ¹H NMR (CDCl₃, 400 MHz) δ 8.34 (s, 1H), 7.86 (s, 1H),7.59-7.28 (m, 12H), 6.75 (d, J=8.8 Hz, 1H), 4.45 (s, 2H).

Compound 72: ¹H NMR (CDCl₃, 400 MHz) δ 8.34 (s, 1H), 7.80 (s, 1H),7.60-7.40 (m, 7H), 6.74 (d, J=8.8 Hz, 1H), 3.15-3.10 (m, 2H), 1.81-1.72(m, 2H), 1.481-1.40 (m, 2H), 0.98-0.93 (m, 3H).

XIX-9: To a solution of XIX-5 (1.0 eq) in dioxane/H₂O (v/v=10:1) wasadded Na₂CO₃ (1.5 eq) with stirring at 0° C. for 10 min. Then XIX-8 (1.2eq) was added dropwise. The mixture was stirred at rt for 5 hours. Thereaction was concentrated. The residue was partitioned between EtOAc andH₂O. The organic layer was separated, washed with brine, dried overNa₂SO₄, concentrated. The crude product was purified by prep-TLC (EtOAc)to give XIX-9.

Compound 73: ¹H NMR (DMSO-d₆, 400 MHz) δ 8.80 (s, 1H), 8.33 (s, 1H),8.22 (d, J=2.4 Hz, 1H), 8.01 (dd, J=2.4, 9.6 Hz, 1H), 7.57-7.52 (m, 2H),7.49-7.45 (m, 3H), 6.58 (d, J=9.6 Hz, 1H), 4.44 (q, J=7.2 Hz, 2H), 1.36(t, J=7.2 Hz, 3H).

Compound 74: ¹H NMR (DMSO-d₆, 400 MHz) δ 8.78 (s, 1H), 8.33 (s, 1H),8.22 (d, J=2.4 Hz, 1H), 8.00 (dd, J=2.8, 9.6 Hz, 1H), 7.57-7.53 (m, 2H),7.49-7.46 (m, 3H), 6.58 (d, J=9.6 Hz, 1H), 4.40 (t, J=6.4 Hz, 2H),1.74-1.70 (m, 2H), 1.46-1.39 (m, 2H), 0.94 (t, J=7.2 Hz, 3H).

XIX-11: A mixture of XIX-5 (1 eq.) and XIX-10 (0.5 mmol/mL) was stirredat 90-100° C. under N₂ overnight. The mixture was concentrated. Theresidue was purified by prep-TLC (PE: EtOAc=1:1) to give XIX-11.

Compound 75: ¹H NMR (DMSO-d₆, 300 MHz) δ 8.70 (s, 1H), 8.24-8.21 (m,2H), 8.14 (d, J=2.4 Hz, 1H), 7.95 (dd, J=9.3, 2.4 Hz, 1H), 7.53-7.42 (m,5H), 6.53 (d, J=9.3 Hz, 1H), 3.99-3.92 (m, 1H), 1.18 (s, 3H), 1.15 (s,3H).

Compound 76: ¹H NMR (DMSO-d₆, 300 MHz) δ 8.70 (s, 1H), 8.51 (t, J=6.0Hz, 1H), 8.20 (d, J=0.6 Hz, 1H), 8.13 (d, J=2.1 Hz, 1H), 7.95 (dd,J=9.6, 2.7 Hz, 1H), 7.51-7.42 (m, 5H), 6.53 (d, J=9.3 Hz, 1H), 3.31-3.24(m, 2H), 1.12-1.07 (m, 3H).

XIX-13: To a solution of XIX-5 (1 eq.) in DCM (0.16 mmol/mL) was addedXIX-12 (1.25 eq.) and TEA (3 eq.) at 0° C. Then the mixture was stirredat rt. overnight. The mixture was concentrated, diluted with water,extracted with EtOAc. The combined organic layer was washed with brine,dried over anhydrous Na₂SO₄, and concentrated in vacuo. The residue waspurified by prep-TLC (PE: EA=1:2) to give XIX-13.

Compound 70: ¹H NMR (CDCl₃, 400 MHz) δ 8.19 (s, 1H), 8.04-8.02 (m, 2H),7.82 (s, 1H), 7.69-7.65 (m, 1H), 7.58-7.49 (m, 6H), 7.47-7.45 (m, 1H),7.39-7.37 (m, 2H), 6.72 (d, J=9.2 Hz, 1H). MS (ESI) m/z (M+H)⁺ 378.1.

Compound 71: ¹H NMR (CDCl₃, 400 MHz) δ 8.11 (s, 1H), 7.91 (s, 1H),7.55-7.39 (m, 7H), 6.75 (d, J=9.6 Hz, 1H), 3.35 (s, 3H). MS (ESI) m/z(M+Na)⁺ 338.0.

Example 8 Synthesis of Compounds 77-80 (Scheme XX)

XX-3: XX-1 (1 eq.), XX-2 (1.2 eq.) and K₂CO₃ (1.5 eq.) were dissolved inDMF. The solution was stirred at 50° C. for 6 hrs under N₂ atmosphere.The reaction mixture was diluted with water and extracted with EtOAc.The combined organic phase was washed with brine, dried over Na₂SO₄ andconcentrated to give crude product, it was purified by prep-TLC(PE:EA=1:1) to yield XX-3.

Compound 77 was prepared by reacting 5-(4-fluorophenyl)pyridin-2(1H)-onewith (2-bromoethyl)benzene following the general procedure describedabove. ¹H NMR (CDCl₃, 400 MHz) δ 7.53 (m, 1H), 7.33-7.24 (m, 3H),7.18-7.16 (d, J=6.8 Hz, 2H), 7.09-7.00 (m, 4H), 6.92 (d, J=2.4 Hz, 1H),6.68-6.66 (d, J=9.6 Hz, 1H), 4.23-4.20 (m, 2H), 3.12-3.09 (m, 2H). MS(ESI) m/z (M+H)⁺ 293.9.

Compound 79 was prepared by reacting 5-(4-fluorophenyl)pyridin-2(1H)-onewith (bromomethyl)benzene following the general procedure describedabove. ¹H NMR (CDCl₃, 400 MHz) δ 7.57-7.55 (m, 1H), 7.42-7.41 (d, J=2.8Hz, 1H), 7.38-7.28 (m, 7H), 7.10-7.05 (m, 2H), 6.72-6.70 (d, J=9.2 Hz,1H), 5.22 (s, 2H). MS (ESI) m/z (M+H)⁺ 280.1.

Compound 78 was prepared by reacting 5-methylpyridin-2(1H)-one with(bromomethyl)benzene following the general procedure described above. ¹HNMR (CDCl₃, 400 MHz) δ 7.36-7.27 (m, 5H), 7.19-7.16 (m, 1H), 7.02 (s,1H), 6.58-6.56 (d, J=7.2 Hz, 1H), 5.12 (s, 2H), 2.03 (s, 3H). MS (ESI)m/z (M+H)⁺ 199.8.

Compound 80 was prepared by reacting 5-methylpyridin-2(1H)-one with(2-bromoethyl)benzene following the general procedure described above.¹H NMR (CDCl₃, 400 MHz) δ 7.31-7.21 (m, 3H), 7.18-7.15 (m, 3H), 6.70 (s,1H), 6.54-6.52 (d, J=9.2 Hz, 1H), 4.16-4.08 (m, 2H), 3.06-3.02 (m, 2H),1.96 (s, 3H). MS (ESI) m/z (M+H)⁺ 213.9.

Example 9 Synthesis of Compound 82 (Scheme XXI)

XXI-3 was obtained following the similar procedure for obtaining X-6 asa red solid. ¹H NMR (CDCl₃, 300 MHz) δ 7.52-7.35 (m, 5H), 7.26 (s, 1H),6.82 (d, J=8.1 Hz, 1H), 2.37 (s, 3H).

To the solution of XXI-3 (500 mg, 1.56 mmol) in 10 mL of DMSO was addedhydrazine hydrate (1 mL) at 0° C., The mixture was stirred at 100° C.for 2 hrs. After being cooled, the mixture was quenched with aq. HCl(1M) and stirred for 1 h, extracted with EA (50 mL×3). The combinedorganic layers were washed with brine, dried over anhydrous Na₂SO₄ andconcentrated. The residue was purified by column chromatography onsilica gel (PE/EA=20/1) to afford Compound 82 (50 mg, 11% yield) as awhite solid. ¹H NMR (CDCl₃, 400 MHz) δ 7.48 (d, J=8.8 Hz, 2H), 7.37 (d,J=8.4 Hz, 2H), 7.15 (s, 1H), 7.03 (d, J=8.0 Hz, 1H), 6.70 (d, J=8.0 Hz,1H), 3.69 (s, 2H), 2.35 (s, 3H). MS (ESI) m/z [M+H]⁺ 308.1.

Compound 81 was obtained by reacting indolin-2-one with(4-(trifluoromethoxy)phenyl)boronic acid refluxing in anhydrous DCMunder oxygen atmosphere overnight in the presence of Cu(OAc)₂ and 4 Åmolecular sieve as a white solid. ¹H NMR (CDCl₃, 400 MHz) δ 7.47 (d,J=8.0 Hz, 2H), 7.38-7.32 (m, 3H), 7.23 (t, J=7.6 Hz, 1H), 7.11 (t, J=7.6Hz, 1H), 6.80 (d, J=7.6 Hz, 1H), 3.73 (s, 2H). MS (ESI) m/z [M+H]⁺294.0.

Example 10 Synthesis of Compounds 83 and 84 (Scheme XXII)

XXII-2 was prepared following the similar procedure for obtaining XIX-3as a white solid.

XXII-2 (500 mg, 2.7 mmol) was dissolved in EtOH, the solution wasdegassed with Ar for three times and then Raney Ni was added. Themixture was degassed by Ar and H₂ in turn for three times. The mixturewas stirred at rt for 24 hrs under H₂ (15-20 psi). The reaction wasdetected by LCMS and TLC. The reaction mixture was filtrated and washedwith EA, the filtrate was concentrated and the residue was purified bycolumn chromatography (PE/EA=3/1) and then separated by chiral prep-HPLCto give the two pure optical enantiomer: Compound 83 (149 mg, 30% yield)and Compound 84 (30.3 mg, 6% yield). The absolute chirality of the twocompounds was not identified.

Compound 83: ¹H NMR (CDCl₃, 400 MHz) δ 7.41-7.37 (m, 2H), 7.27-7.23 (m,3H), 3.59-3.54 (m, 1H), 3.36-3.30 (m, 1H), 2.66-2.50 (m, 2H), 2.19-2.10(m, 1H), 2.00-1.94 (m, 1H), 1.67-1.57 (m, 1H), 1.07 (d, J=6.8 Hz, 3H).MS (ESI) m/z (M+H)⁺ 190.0. RT (SFC)=3.99.

Compound 84: ¹H NMR (CDCl₃, 400 MHz) δ 7.41-7.37 (m, 2H), 7.27-7.23 (m,3H), 3.59-3.55 (m, 1H), 3.36-3.31 (m, 1H), 2.66-2.50 (m, 2H), 2.19-2.10(m, 1H), 2.00-1.94 (m, 1H), 1.67-1.57 (m, 1H), 1.07 (d, J=6.8 Hz, 3H).MS (ESI) m/z (M+H)⁺ 190.0. RT (SFC)=4.18.

Example 11-A Synthesis of Compounds 85-87 (Scheme XXIII)

XXIII-1 (15 g, 0.1 mol) was dissolved in anhydrous DMF (80 mL), and thenfreshly prepared sodium methoxide (24 g, 0.44 mol) was added. Theresulting mixture was stirred at 110-120° C. for 12 hrs under N₂. Cooledto rt, diluted with EA (800 mL) and washed with water and brine, driedover Na₂SO₄, concentrated. The residue was purified by flash columnchromatography (PE/EA=10:1) to give XXIII-2 (7.5 g, 54% yield) as acolorless oil.

The mixture of XXIII-2 (7.4 g, 53 mmol) and N-bromosuccinimide (9.3 g,52 mmol) in anhydrous CH₃CN (250 mg) was stirred at 70-85° C. for 12 hrsin dark. Cooled to rt, the mixture was concentrated and the residue waspurified by flash column chromatography (PE/EA=50/1) to give XXIII-3(8.3 g, 72% yield) as a white solid.

XXIII-3 (16.0 g, 38.2 mmol), XXIII-4 (13.4 g, 95.9 mmol) and K₂CO₃ (36.6g, 265.3 mmol) were dissolved in a mixture of DME/H₂O (250 mL/25 mL).The solution was degassed by N₂ for three times and then Pd(PPh₃)₄ (8.5g, 7.37 mmol) was added. The reaction mixture was stirred at 90-100° C.for 10 h under N₂ and then cooled to rt, diluted with AcOEt andfiltered, the filtrate was washed with brine. The separated organicphase was dried over Na₂SO₄, concentrated. The residue was purified byflash column chromatography (PE/EA=20:1˜5:1) to give XXIII-5 (16.0 g,93% yield).

A solution of XXIII-5 (15.0 g, 64.4 mmol) in aq.HBr (48%, 250 mL) wasstirred at 100° C. for 7 h. Then the mixture was cooled to rt, theformed precipitate was filtrated, washed with water to give XXIII-6(17.6 g, yield 91%) as a white solid, which would be utilized in nextstep without any further purification.

To a solution of XXIII-6 (4.6 g, 21 mmol) in DCM (180 mL), copper (II)acetate (7.42 g, 41 mmol), XXIII-7 (8.65 g, 42 mmol), pyridine (10 mL),pyridine-N-oxide (7.8 g, 82 mmol) and 4 Å molecular sieves (3.0 g) wereadded. The mixture was stirred at rt for 38 hrs under O₂ atmosphere. Themixture was filtered; the filtrate was washed with brine, dried overNa₂SO₄, concentrated. The residue was purified by flash columnchromatography (PE/EA=1/1) to give Compound 85 (3.7 g, 46% yield) as awhite solid. ¹H NMR (CD₃OD, 400 MHz) δ 7.57-7.55 (m, 3H), 7.47-7.44 (m,4H), 7.13-7.09 (m, 2H), 6.12 (s, 1H), 3.90 (s, 3H). MS (ESI) m/z (M+H)⁺380.0.

To a solution of Compound 85 (2.0 g, 5.26 mmol) in dry DCM (25 mL) wasadded BBr₃ (2.63 g, 10.52 mmol) dropwise at −65° C.˜−70° C. Afteraddition, the mixture was stirred at 5-8° C. for 12 h, but the startingmaterial still remained. More BBr₃ (5.26 g, 21 mmol) was added dropwiseat −65° C.˜−70° C., after that, the mixture was stirred at 25-30° C. for24 hrs. And then the mixture was cooled to 0° C. under ice-water bath,quenched with methanol by dropwise addition until no smoke appeared.Then the mixture was concentrated, the residue was basified to pH 8-9with saturated aq.NaHCO₃, extracted with EA (50 mL×3), washed withbrine, dried over Na₂SO₄, concentrated. The residue was purified byflash column chromatography (PE/EtOAc=1/2) to give Compound 86 (1.2 g,52% yield) as a white solid. ¹H NMR (CD₃OD, 400 MHz) δ 7.58-7.49 (m,5H), 7.45-7.43 (m, 2H), 7.13-7.09 (m, 2H), 6.01 (s, 1H). MS (ESI) m/z(M+H)⁺ 366.0.

To a solution of Compound 86 (3.3 g, 9.0 mmol) in POCl₃ (60 mL) wasadded N, N-Dimethylaniline (1.5 g, 12.4 mmol). The resulting mixture wasstirred at 100° C. for 2 hrs, cooled to rt, distilled most of POCl₃,quenched with ice-water, and then basified to pH 7-8 with saturated aq.NaHCO₃, and extracted with EA (50 mL×3). The combined organic phase waswashed with brine, dried over Na₂SO₄ and concentrated. The residue waspurified by flash chromatography (PE:EA=5:1) to give Compound 87 (2.0 g,58% yield) as a light yellow solid. ¹H NMR (CD₃OD, 400 MHz) δ 7.72 (s,1H), 7.61-7.58 (m, 2H), 7.48-7.44 (m, 4H), 7.19-7.15 (m, 2H), 6.85 (s,1H). MS (ESI) m/z (M+H)⁺ 384.0.

Compound 88: Compound 87 was dissolved in 4-methoxybenzylamine (2 mL),the mixture was stirred at 180° C. for 2.5 h under N₂. After beingcooled to rt, the mixture was diluted with EA (60 mL), washed withaq.HCl (2 M) with brine, dried over Na₂SO₄ and concentrated. The residuewas purified by prep-TLC (PE:EA=1:2) to give an intermediate (47 mg, 50%yield) which was further dissolved in TFA (2 mL) and stirred at rt for 3h. Then it was diluted with water and basified to pH 8-9 with saturatedaq. NaHCO₃, extracted with EA (30 mL×3). The combined organic layer waswashed with brine, dried over anhydrous Na₂SO₄ and concentrated. Theresidue was purified by prep-TLC (PE/EA=1/3) to give Compound 88 (30 mg,79% yield). ¹H NMR (CD₃OD, 400 MHz) δ 7.53-7.51 (m, 2H), 7.45-7.40 (m,4H), 7.32 (s, 1H), 7.19 (t, J=8.8 Hz, 2H), 5.78 (s, 1H).

Compound 89: A mixture of Compound 87 (75 mg, 0.2 mmol) in benzylamine(1 mL) was stirred at 180° C. for 4 hrs, then it was cooled to rt andpurified by flash column chromatography (PE:AE=1:1) to give Compound 89(80 mg, 90% yield). ¹H NMR (CDCl₃, 400 MHz) δ 7.47-7.44 (m, 2H),7.38-7.34 (m, 4H), 7.31-7.27 (m, 5H), 7.16-7.12 (m, 2H), 7.06 (s, 1H),5.70 (s, 1H), 4.59 (t, J=5.2 Hz, 1H), 4.34 (d, J=5.2 Hz, 2H). MS (ESI)m/z (M+H)⁺ 455.3.

Compound 90 was prepared following the similar procedure for obtainingCompound 88 using 1-(4-methoxyphenyl)-N-methylmethanamine in place of4-methoxybenzylamine. ¹H NMR (CDCl₃, 400 MHz) δ 7.47-7.45 (m, 2H),7.34-7.28 (m, 4H), 7.17-7.12 (m, 2H), 7.03 (s, 1H), 5.65 (s, 1H), 4.28(m, 1H), 2.83 (d, J=4.8 Hz, 3H). MS (ESI) m/z (M+H)⁺ 379.0.

Compounds 104 and 107-110 were prepared by the reaction of Compound 88(1 eq.) with the relevant acyl chloride (1.1 eq.) in DCM and pyridine (5eq.). The mixture was stirred at rt overnight.

Compound 104: ¹H NMR (CDCl₃, 400 MHz) δ 7.76 (s, 1H), 7.47 (d, J=8.8 Hz,2H), 7.36-7.30 (m, 4H), 7.23-7.19 (m, 3H), 6.96 (s, 1H), 2.06 (s, 3H).

Compound 107: ¹H NMR (CDCl₃, 400 MHz) δ 7.78 (s, 1H), 7.47 (d, J=8.8 Hz,2H), 7.35-7.31 (m, 4H), 7.24-7.19 (m, 3H), 6.95 (s, 1H), 2.22 (t, J=7.6Hz, 2H), 1.59-1.51 (m, 2H), 1.36-1.26 (m, 2H), 0.89 (t, J=7.2 Hz, 3H).

Compound 108: ¹H NMR (CDCl₃, 400 MHz) δ 7.79 (s, 1H), 7.47 (d, J=8.8 Hz,2H), 7.36-7.31 (m, 4H), 7.25-7.20 (m, 3H), 7.02 (s, 1H), 2.39-2.32 (m,1H), 1.12 (d, J=6.8 Hz, 2H).

Compound 109: ¹H NMR (CDCl₃, 300 MHz) δ 7.81 (s, 1H), 7.50-7.46 (m, 2H),7.38-7.33 (m, 4H), 7.25-7.21 (m, 3H), 6.97 (s, 1H), 2.24 (t, J=7.5 Hz,2H), 1.59 (t, J=6.9 Hz, 2H), 1.32-1.26 (m, 4H), 0.89 (t, J=6.9 Hz, 3H).

Compound 110: ¹H NMR (CDCl₃, 400 MHz) δ 7.78 (s, 1H), 7.47 (d, J=8.8 Hz,2H), 7.35-7.31 (m, 4H), 7.24-7.20 (m, 3H), 6.94 (s, 1H), 2.20 (t, J=7.6Hz, 2H), 0.93 (t, J=7.6 Hz, 3H).

Compound 106: To a solution of Compound 88 (120 mg, 0.33 mmol) intoluene (3 mL) was added propionic anhydride (50 mg, 0.38 mmol). Themixture was heated to reflux overnight. The reaction was concentrated toremove toluene. The residue was purified by prep-HPLC to give Compound106 (38.2 mg, 28% yield). ¹H NMR (CDCl₃, 400 MHz) δ 7.78 (s, 1H), 7.46(d, J=8.8 Hz, 2H), 7.36-7.31 (m, 4H), 7.24-7.20 (m, 3H), 6.96 (s, 1H),2.27 (q, J=7.6 Hz, 2H), 1.11 (t, J=7.6 Hz, 3H).

Compounds 105, 112 and 113 were prepared by reacting Compound 88 withthe relevant chloroformate in LiHMDS and THF.

Compound 105: ¹H NMR (CDCl₃, 400 MHz) δ 7.48-7.45 (m, 3H), 7.34-7.30 (m,4H), 7.23-7.17 (m, 3H), 6.46 (s, 1H), 4.12 (d, J=6.8 Hz, 2H), 1.70-1.63(m, 2H), 0.93 (t, J=7.6 Hz, 3H).

Compound 112: ¹H NMR (CDCl₃, 400 MHz) δ 7.49-7.41 (m, 3H), 7.34-7.30 (m,4H), 7.23-7.16 (m, 3H), 6.41 (s, 1H), 5.05-4.98 (m, 1H), 1.26 (d, J=6.4Hz, 6H).

Compound 113: ¹H NMR (CDCl₃, 400 MHz) δ 7.53 (s, 1H), 7.49 (d, J=9.2 Hz,4H), 7.41-7.37 (m, 4H), 7.34 (d, J=8.4 Hz, 2H), 7.28-7.14 (m, 3H),7.15-7.12 (m, 2H), 6.81 (s, 1H).

Compound 91: To a solution of Compound 86 (250 mg, 0.7 mmol) in dry DMF(5 mL) was added BnBr (128 mg, 0.77 mmol) and Na₂CO₃ (112 mg, 1.1 mmol),the reaction mixture was stirred at rt overnight. And then it wasdiluted with water (10 mL), extracted by ethyl acetate (30 mL×3). Thecombined extract was washed with brine and water, dried over Na₂SO4,concentrated to give crude product. The crude product was purified byflash chromatography (PE/EA=5/1) to give Compound 91 (60 mg, 19% yield).¹H NMR (CD₃OD, 400 MHz) δ 7.59-7.56 (m, 3H), 7.53-7.49 (m, 2H), 7.46 (d,J=8.4 Hz, 2H), 7.40-7.33 (m, 5H), 7.14-7.09 (m, 2H), 6.23 (s, 1H), 5.23(s, 2H). MS (ESI) m/z (M+H)⁺ 456.1.

Compounds 92-100 were prepared by reacting Compound 87 with the relevantalcohol (1 eq.) in DMF and NAH (1.5 eq.) at rt for 2 hrs. After thereaction mixture was quenched with water and extract with EA, theorganic phase was washed with brine, dried over Na₂SO₄ and concentratedin vacuo. The residue was purification by prep-TLC to give the finalproduct.

Compound 92: ¹H NMR (CDCl₃, 400 MHz) δ 7.47-7.45 (m, 2H), 7.41-7.37 (m,2H), 7.35-7.33 (m, 2H), 7.24 (m, 1H), 7.08-7.04 (m, 2H), 6.06 (s, 1H),4.15-4.12 (m, 2H), 3.69-3.66 (m, 4H), 2.76-2.74 (m, 2H), 2.47-2.45 (m,4H). MS (ESI) m/z (M+H)⁺ 479.2.

Compound 93: ¹H NMR (CDCl₃, 400 MHz) δ 7.47-7.45 (m, 2H), 7.38-7.32 (m,4H), 7.23 (s, 1H), 7.09-7.05 (m, 2H), 6.06 (s, 1H), 4.30 (m, 2H), 3.06(m, 2H), 2.70 (m, 4H), 1.84 (m, 4H). MS (ESI) m/z (M+H)⁺ 463.1.

Compound 94: ¹H NMR (CDCl₃, 400 MHz) δ 7.47-7.45 (m, 2H), 7.36-7.32 (m,4H), 7.24 (m, 1H), 7.09-7.05 (m, 2H), 6.04 (s, 1H), 4.11-4.09 (m, 2H),2.98-2.93 (m, 10H). MS (ESI) m/z (M+H)⁺ 527.0.

Compound 95: ¹H NMR (CDCl₃, 400 MHz) δ 7.47-7.45 (m, 2H), 7.37-7.32 (m,4H), 7.26 (s, 1H), 7.11-7.07 (m, 2H), 6.06 (s, 1H), 4.58 (m, 1H), 2.62(m, 4H), 2.42 (s, 3H), 2.27 (m, 2H), 2.02 (m, 2H). MS (ESI) m/z (M+H)⁺463.1.

Compound 96: ¹H NMR (CDCl₃, 400 MHz) δ 7.47-7.45 (m, 2H), 7.42-7.39 (m,2H), 7.35-7.33 (m, 2H), 7.25 (s, 1H), 7.09-7.05 (m, 2H), 6.06 (s, 1H),4.15 (t, J=4.4 Hz, 2H), 3.72 (t, J=4.4 Hz, 2H), 3.37 (s, 3H). MS (ESI)m/z (M+H)⁺ 424.1.

Compound 97: ¹H NMR (CDCl₃, 400 MHz) δ 7.47-7.45 (m, 2H), 7.36-7.32 (m,4H), 7.23 (s, 1H), 7.10-7.06 (m, 2H), 6.04 (s, 1H), 4.15-4.12 (m, 2H),3.65-3.62 (m, 2H), 3.17-3.13 (m, 2H), 2.32-2.28 (m, 2H), 2.91-1.84 (m,2H). MS (ESI) m/z (M+H)⁺ 477.1.

Compound 98: ¹H NMR (CDCl₃, 400 MHz) δ 7.47-7.44 (m, 2H), 7.35-7.32 (m,4H), 7.23 (s, 1H), 7.10-7.06 (m, 2H), 6.04 (s, 1H), 4.22-4.19 (m, 2H),4.10 (s, 2H), 3.73-3.71 (m, 2H), 3.62-3.59 (m, 2H), 3.11-3.08 (m, 2H).MS (ESI) m/z (M+H)⁺ 492.9.

Compound 99: ¹H NMR (CDCl₃, 400 MHz) δ 7.47-7.44 (m, 2H), 7.36-7.29 (m,5H), 7.14-7.10 (m, 2H), 6.06 (s, 1H), 4.72 (s, 1H), 3.05-2.91 (m, 4H),2.53-2.39 (m, 4H). MS (ESI) m/z (M+H)⁺ 498.0.

Compound 100: ¹H NMR (CDCl₃, 400 MHz) δ 7.47-7.45 (m, 2H), 7.39-7.32 (m,4H), 7.24 (s, 1H), 7.09-7.04 (m, 2H), 6.05 (s, 1H), 4.14-4.11 (m, 2H),2.83-2.80 (m, 2H), 2.69 (brm, 4H), 2.49 (s, 3H). MS (ESI) m/z (M+H)⁺492.1.

Compound 102: To a stirred mixture of Compound 87 (200 mg, 0.521 mmol),phenol (59 mg, 0.625 mmol), and K₃PO₄ (331 mg, 1.56 mmol) in THF (5 mL)was added Pd₂(dba)₃ (96 mg, 0.104 mmol). The mixture was purged withnitrogen for three times and then heated to reflux overnight. Themixture was concentrated to remove THF, diluted with H₂O, extracted withEtOAc (30 mL×3), the organic layer was washed with brine, dried overanhydrous Na₂SO₄, and concentrated in vacuo, the crude product waspurified by prep-HPLC to give Compound 102 (158 mg, 69% yield) as ayellow solid. ¹H NMR: (CDCl₃, 400 MHz) δ 7.53-7.42 (m, 6H), 7.35-7.33(m, 3H), 7.30-7.26 (m, 1H), 7.14-7.09 (m, 4H), 5.82 (s, 1H).

Compound 541 was prepared following the similar procedure described inthe synthesis of Compound 85 by reacting4-chloro-5-(4-fluorophenyl)pyridin-2(1H)-one with 2-methyl-4-ethoxyboronic acid. ¹H NMR (DMSO-d₆, 400 MHz) δ 7.66 (s, 1H), 7.49 (m, 2H),7.28-7.20 (m, 3H), 6.93 (s, 1H), 6.93-6.87 (m, 1H), 6.81 (s, 1H), 4.05(q, J=6.8 Hz, 2H), 2.06 (s, 3H), 1.33 (t, J=6.8 Hz, 3H). MS (ESI) m/z(M+H)⁺ 358.0.

Compound 551 was prepared by reacting Compound 541 with 2-methoxyethanolin DMF and KOH at 150° C. overnight. ¹H NMR (CDCl₃, 400 MHz) δ 7.45-7.39(m, 2H), 7.14-7.02 (m, 4H), 6.85-6.80 (m, 2H), 6.07 (s, 1H), 4.14 (t,J=4.4 Hz, 2H), 4.04 (q, J=7.2 Hz, 2H), 3.72 (t, J=4.4 Hz, 2H), 3.38 (s,3H), 2.16 (s, 3H), 1.42 (t, J=7.2 Hz, 3H). MS (ESI) m/z (M+H)⁺ 398.2.

Compound 550 was prepared following the similar procedure for thesynthesis of Compound 551 using4-chloro-2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridine in place ofXXIII-5. ¹H NMR (CDCl₃, 400 MHz) δ 7.69 (s, 1H), 7.63 (s, 1H), 7.29 (s,1H), 7.11 (d, J=8.4 Hz, 1H), 6.85-7.96 (m, 2H), 6.05 (s, 1H), 4.18 (t,J=4.4 Hz, 2H), 4.06 (q, J=6.8 Hz, 2H), 3.91 (s, 3H), 3.82 (t, J=4.4 Hz,2H), 3.48 (s, 3H), 2.14 (s, 3H), 1.42 (t, J=6.8 Hz, 3H). MS (ESI) m/z(M+H)⁺ 384.1.

Example 11-B Synthesis of Compound 101 (Scheme XXIV)

To the solution of XXIV-1 (20 g, 85.5 mmol) in DMF (100 mL) was addedNaH (60%, 4.1 g, 103 mmol) in portions. The mixture was stirred at rtfor 30 min. Then XXIV-2 (14.3 g, 85.5 mmol) was added. The reaction wasstirred at rt overnight. The reaction was quenched with ice-watercarefully, and then extracted with EtOAc (100 mL×2). The combinedorganic layer was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated. The residue was used for next step directly (40 g, 140%crude yield).

To the solution of XXIV-3 (6.8 g, 21.25 mmol) in MeOH (50 mL) was addedK₂CO₃ (8.8 g, 64 mmol). The mixture was stirred at rt for 2 hrs. Thenconcentrated, diluted with H₂O, extracted with EtOAc (100 mL×2). Thecombined organic layer was washed with brine, dried over anhydrousNa₂SO₄ and concentrated. The crude product was used directly (3.0 g, 51%yield).

To the solution of XXIV-4 (900 mg, 3.24 mmol) in DMF (10 mL) was addedNaH (60%, 160 mg, 3.9 mmol). The mixture was stirred at rt for 30 min.Then Compound 87 (1.25 g, 3.24 mmol) was added. The reaction was stirredat rt overnight. LCMS showed the reaction was completed. The reactionwas quenched with ice-water carefully, and then extracted with EtOAc (30mL×3). The combined organic layer was washed with brine, dried overanhydrous Na₂SO₄ and concentrated to give XXIV-6 (140 mg, 22% yield).

A mixture of XXIV-6 (140 mg, 0.224 mmol) and Pd/C in ethanol (5 mL) wasstirred under H₂ at rt for 4 hours. Filtered the reaction, andconcentrated. The residue was purified by prep-HPLC to afford Compound101 (30.9 mg, 28% yield). ¹H NMR (CDCl₃, 400 MHz) δ 7.45-7.40 (m, 2H),7.36-7.31 (m, 4H), 7.26 (m, 1H), 7.11-7.07 (m, 2H), 6.14 (s, 1H), 4.18(m, 2H), 3.75-3.70 (m, 4H), 3.30 (m, 2H), 3.07 (m, 2H).

Example 11-C Synthesis of Compounds 117 and 118 (Scheme XXV)

XXV-6 was obtained following the synthetic scheme as described above. MS(ESI) m/z (M+H)⁺ 231.95.

XXV-10 was prepared following the similar procedure for obtainingCompound 40. ¹HNMR (CDCl₃, 400 MHz) δ 7.50-7.42 (m, 2H), 7.40-7.31 (m,4H), 7.26-7.20 (m, 1H), 7.10-7.03 (m, 3H), 3.73 (s, 3H).

Compound 117: The mixture of XXV-10 (1.0 g, 2.5 mmol), LiOH.H₂O (1.0 g,24 mmol) in MeOH/H₂O (15 mL/3 mL) was stirred at rt overnight. Themixture was evaporated and then acidified with aq. HCl (2 M) to pH=4-5,extracted with EtOAc (30 mL×3). The combined organic layer was washedwith brine, dried over anhydrous Na₂SO₄ and concentrated. The residuewas purified by prep-HPLC to give Compound 117 (806 mg, 83% yield) as awhite solid. ¹H NMR (DMSO-d₆, 400 MHz) δ 7.80 (s, 1H), 7.72-7.67 (m,2H), 7.57-7.53 (m, 2H), 7.43-7.38 (m, 2H), 7.25-7.20 (m, 2H), 6.75 (s,1H). MS (ESI) m/z [M+H]⁺ 394.0.

Compound 118: To a solution of Compound 117 (98.2 mg, 0.25 mmol) in dryDCM (40 mL) was added benzyl amine (29 mg, 0.28 mmol), followed byadding HATU (105 mg, 0.28 mmol) and DIEA (65 mg, 0.5 mmol). The reactionmixture was stirred at rt overnight. The resulting mixture wasconcentrated to remove solvent, diluted with EtOAc (50 mL), washed with5% citric acid, sat. aq. NaHCO₃ and brine, dried over Na₂SO₄,concentrated to give crude product. The crude product was purified byprep-TLC (PE: EA=5:1) to yield Compound 118 (10 mg, 8.3% yield) as ayellow solid. ¹HNMR (CD₃OD, 400 MHz) δ 7.69 (s, 1H), 7.60 (d, J=8.8 Hz,2H), 7.48 (d, J=8.4 Hz, 2H), 7.34-7.26 (m, 5H), 7.12-7.10 (m, 2H),7.02-6.98 (m, 2H), 6.69 (s, 1H), 4.38 (s, 2H). MS (ESI) m/z (M+H)⁺483.1.

General procedure for preparing Compounds 103, 111, and 114: To amixture of Compound 117 (1 eq.) in toluene was added TEA (2.6 eq.) and 4Å molecular sieve. The mixture was stirred at 100° C. for 1 h, then DPPA(1.05 eq.) and the relevant alcohol (1.2 eq.) was added under N₂protection. The reaction mixture was stirred at 110° C. overnight. Themixture was concentrated, diluted with H₂O, extracted with EtOAc. Thecombined organic layer was washed with water and brine, dried overanhydrous Na₂SO₄, and concentrated in vacuo, the residue was purified byprep-TLC (PE:EA=2:1) to give the final product.

Compound 103: ¹H NMR (CDCl₃, 400 MHz) δ 7.52 (s, 1H), 7.49-7.45 (m, 2H),7.44-7.26 (m, 9H), 7.22-7.15 (m, 3H), 6.53 (s, 1H), 5.18 (s, 2H). MS(ESI) m/z [M+H]⁺ 499.0.

Compound 111: ¹H NMR (CDCl₃, 400 MHz) δ 7.47-7.45 (m, 3H), 7.33-7.30 (m,4H), 7.21-7.17 (m, 3H), 6.50 (s, 1H), 3.76 (s, 3H). MS (ESI) m/z [M+H]⁺422.0.

Compound 114: ¹H NMR (CDCl₃, 400 MHz) δ 7.50-7.45 (m, 3H), 7.35-7.30 (m,4H), 7.22-7.17 (m, 3H), 6.46 (s, 1H), 4.21 (q, J=6.8 Hz, 2H), 1.28 (t,J=6.8 Hz, 3H). MS (ESI) m/z [M+H]⁺ 436.1.

General procedure for preparing Compounds 115 and 116: To the solutionof Compound 117 (1 eq.) in toluene was added TEA (2.5 eq) and 4 Åmolecular sieve (100 mg). The mixture was heated to 100° C. for 30minutes. Then cooled to 80° C., the relevant amine (1.2 eq.) and DPPA(1.2 eq) were added. The mixture was heated to 110° C. for 3 hrs. Themixture was filtered, diluted with water, extracted with EtOAc. Thecombined organic layer was washed with brine, dried over anhydrousNa₂SO₄ and concentrated. The residue was purified by Prep-HPLC to givethe final product.

Compound 115: ¹H NMR (400 MHz, CDCl₃) δ 7.46-7.44 (m, 2H), 7.35-7.30 (m,5H), 7.20-7.15 (m, 3H), 6.09 (s, 1H), 4.77 (s, 1H), 3.13 (d, J=6.0 Hz,2H), 1.51 (m, 2H), 0.90 (t, J=7.2 Hz, 3H).

Compound 116: ¹H NMR (CDCl₃, 400 MHz) δ 7.33 (s, 2H), 7.26-7.22 (m, 5H),7.21-7.17 (m, 6H), 7.03-6.97 (m, 3H), 6.90 (brs, 1H), 4.24 (d, J=5.2 Hz,2H).

Compound 119 was prepared following the similar procedure for obtainingCompound 85 using (4-ethoxy-2-methylphenyl)boronic acid in place ofXXIII-7. ¹H NMR (CDCl₃, 400 MHz) δ 7.38-7.34 (m, 2H), 7.13-7.11 (m, 2H),7.08-7.04 (m, 2H), 6.84-6.78 (m, 2H), 6.10 (s, 1H), 4.04 (q, J=7.2 Hz,2H), 3.85 (s, 3H), 2.17 (s, 3H), 1.42 (t, J=7.2 Hz, 3H). MS (ESI) m/z(M+H)⁺ 353.9.

Compound 120 was prepared following the similar procedure for obtainingCompound 85 using1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole inplace of XXIII-4 as a white solid. ¹H NMR (CD₃OD, 400 MHz) δ 7.61 (m,2H), 7.47-7.43 (m, 2H), 7.38-7.33 (m, 3H), 6.07 (s, 1H), 3.93 (s, 3H),3.91 (s, 3H). MS (ESI) m/z (M+H)⁺ 365.9.

Compound 121 was prepared following the similar procedure for obtainingCompound 86. ¹H NMR (DMSO-d₆, 400 MHz) δ 7.97 (s, 1H), 7.82 (s, 1H),7.76 (s, 1H), 7.55-7.53 (m, 2H), 7.48-7.46 (m, 2H), 6.00 (s, 1H), 3.89(s, 3H). MS (ESI) m/z (M+H)⁺ 352.0.

Compound 122 was prepared following the similar procedure for obtainingCompound 87. ¹H NMR (CD₃OD, 400 MHz) δ 7.88 (s, 1H), 7.81 (s, 1H), 7.68(s, 1H), 7.59-7.57 (m, 2H), 7.48-7.46 (m, 2H), 6.84 (s, 1H), 4.90 (s,3H). MS (ESI) m/z (M+H)⁺ 370.1.

General procedure for preparing Compounds 123, 126-129, 131-135, 160 and161: A mixture of Compound 122 (200 mg, 0.542 mmol) in the relevantamine (1 mL) was stirred at 130-160° C. for 4 hrs. After being cooled tort, the mixture was diluted with H₂O, extracted with EtOAc, the organiclayer was washed with water and brine, dried over anhydrous Na₂SO₄, andconcentrated in vacuo, the crude product was purified by flash columnchromatography (PE:AE=1:3) to give the final product.

Compound 123: ¹H NMR (CD₃OD, 400 MHz) δ 7.82 (s, 1H), 7.64 (s, 1H),7.51-7.47 (m, 2H), 7.42-7.38 (m, 2H), 7.36-7.35 (m, 5H), 7.28-7.25 (m,1H), 5.53 (s, 1H), 4.45 (d, J=4.4 Hz, 2H), 3.97 (s, 3H). MS (ESI) m/z(M+H)⁺ 441.1.

Compound 126: ¹H NMR (CDCl₃, 400 MHz) δ 7.55 (s, 1H), 7.50-7.45 (m, 2H),7.40 (s, 1H), 7.33-7.28 (m, 4H), 7.25 (m, 1H), 7.13-7.09 (m, 3H), 6.00(s, 1H), 4.16 (s, 2H), 3.81 (s, 3H), 2.65 (s, 3H). MS (ESI) m/z (M+H)⁺455.

Compound 127: ¹H NMR (CDCl₃, 400 MHz) δ 7.61 (s, 1H), 7.55 (s, 1H),7.46-7.42 (m, 2H), 7.32-7.28 (m, 2H), 7.12 (s, 1H), 6.05 (s, 1H), 3.93(s, 3H), 2.91 (m, 4H), 1.56 (m, 6H). MS (ESI) m/z (M+H)⁺ 419.

Compound 128: ¹H NMR (CDCl₃, 400 MHz) δ 7.63 (s, 1H), 7.52 (s, 1H),7.45-7.41 (m, 2H), 7.32-7.28 (m, 2H), 7.12 (s, 1H), 6.06 (s, 1H), 3.92(s, 3H), 3.70 (m, 4H), 2.96 (m, 4H). MS (ESI) m/z (M+H)⁺ 421.1.

Compound 129: ¹H NMR (CDCl₃, 400 MHz) δ 7.60 (s, 1H), 7.51 (s, 1H),7.48-7.45 (m, 2H), 7.33-7.30 (m, 2H), 7.20-7.17 (m, 3H), 7.13-7.11 (m,1H), 7.08-7.05 (m, 1H), 6.23 (s, 1H), 4.23 (s, 2H), 3.89 (s, 3H), 3.28(t, J=6.0 Hz, 2H), 2.77 (t, J=6.0 Hz, 2H). MS (ESI) m/z (M+H)⁺ 467.1.

Compound 131: ¹H NMR (CDCl₃, 400 MHz) δ 7.45-7.41 (m, 2H), 7.37-7.26 (m,6H), 7.18-7.16 (m, 2H), 7.08 (s, 1H), 7.02 (s, 1H), 5.70 (s, 1H), 4.43(t, J=6.4 Hz, 1H), 3.88 (s, 3H), 3.42 (q, J=6.4 Hz, 2H), 2.93 (t, J=6.4Hz, 3H). MS (ESI) m/z (M+H)⁺ 454.0.

Compound 132: ¹H NMR (CDCl₃, 400 MHz) δ 7.49 (s, 1H), 7.45-7.42 (m, 2H),7.39-7.33 (m, 3H), 7.31-7.24 (m, 3H), 7.05 (s, 1H), 5.90 (s, 1H),4.61-4.55 (m, 3H), 3.91 (s, 3H). MS (ESI) m/z (M+H)⁺ 508.0.

Compound 133: ¹H NMR (CDCl₃, 400 MHz) δ 7.49 (s, 1H), 7.44-7.39 (m, 3H),7.30-7.26 (m, 3H), 7.04 (s, 1H), 6.95-6.90 (m, 2H), 5.81 (s, 1H), 4.79(t, J=6.0 Hz, 1H), 4.41 (d, J=6.0 Hz, 2H), 3.94 (s, 3H). MS (ESI) m/z(M+H)⁺ 477.1.

Compound 134: ¹H NMR (CDCl₃, 400 MHz) δ 7.51 (s, 1H), 7.45-7.39 (m, 3H),7.30-7.25 (m, 2H), 7.22-7.20 (m, 2H), 7.06 (s, 1H), 6.90-6.87 (m, 2H),5.70 (s, 1H), 4.70 (t, J=5.2 Hz, 1H), 4.25 (d, J=5.2 Hz, 2H), 3.93 (s,3H), 3.81 (s, 3H). MS (ESI) m/z (M+H)⁺ 471.2.

Compound 135: ¹H NMR (CDCl₃, 400 MHz) δ 7.56 (s, 1H), 7.48-7.42 (m, 3H),7.32-7.30 (m, 2H), 7.13 (s, 1H), 7.03-7.00 (m, 2H), 6.85-6.81 (m, 2H),5.98 (s, 1H), 4.08 (s, 2H), 3.85 (s, 3H), 3.79 (s, 3H), 2.59 (s, 3H). MS(ESI) m/z (M+H)⁺ 485.0.

Compound 160: ¹H NMR (CDCl₃, 400 MHz) δ 8.56-8.55 (m, 2H), 7.61 (d,J=8.0 Hz, 1H), 7.52 (s, 1H), 7.43-7.41 (m, 3H), 7.31-7.28 (m, 3H), 7.08(s, 1H), 5.64 (s, 1H), 4.82 (t, J=5.6 Hz, 1H), 4.37 (d, J=5.6 Hz, 2H),3.94 (s, 3H). MS (ESI) m/z (M+H)⁺ 442.0.

Compound 161: ¹H NMR (CDCl₃, 400 MHz) δ 8.53 (d, J=4.4 Hz, 1H),7.71-7.67 (m, 1H), 7.61 (s, 1H), 7.54 (s, 1H), 7.46-7.44 (m, 2H),7.30-7.27 (m, 3H), 7.23-7.20 (m, 1H), 7.11 (s, 1H), 6.10 (t, J=4.4 Hz,1H), 5.67 (s, 1H), 4.44 (d, J=4.4 Hz, 2H), 3.98 (s, 3H). MS (ESI) m/z(M+H)⁺ 442.0.

Compound 124: Compound 134 (200 mg, 0.42 mmol) was dissolved in TFA (3mL). The solution was stirred at rt for 3 days under N₂. After thematerial was consumed, most of TFA was evaporated, the remaining mixturewas diluted with water and neutralized with saturated aq. NaHCO₃,extracted with EA (30 mL×3), the organic phase was washed with brine,dried over Na₂SO₄, concentrated. The residue was purified by prep-TLC(PE/EA=1/3) to give Compound 124 (50 mg, 34% yield). ¹H NMR (CDCl₃, 400MHz) δ 7.54 (s, 1H), 7.45-7.43 (m, 3H), 7.31-7.29 (m, 2H), 7.12 (s, 1H),5.80 (s, 1H), 4.39 (brs, 2H), 3.96 (s, 3H). MS (ESI) m/z (M+H)⁺ 350.9.

Compound 125 was prepared from Compound 135 following the similarprocedure for obtaining Compound 124. ¹H NMR (CDCl₃, 400 MHz) δ 7.50 (s,1H), 7.45-7.41 (m, 3H), 7.30-7.28 (m, 2H), 7.04 (s, 1H), 5.63 (s, 1H),4.50 (t, J=4.8 Hz, 1H), 3.95 (s, 3H), 2.83 (d, J=4.8 Hz, 3H). MS (ESI)m/z (M+H)⁺ 364.9.

Compound 130: To a stirred mixture of Compound 122 (100 mg, 0.271 mmol,1 eq.), aniline (76 mg, 0.81 mmol, 3.0 eq), Xantphos (8 mg, 0.0135 mmol,0.05 eq.), and K₃PO₄ (57 mg, 0.271 mmol, 1.0 eq.) in DMF (2 mL) wasadded Pd₂(dba)₃ (12 mg, 0.0135 mmol, 0.05 eq.). The mixture was purgedwith nitrogen for three times and then heated at 100° C. under nitrogenovernight. After being cooled to rt, the mixture was diluted with H₂O(10 mL), extracted with EtOAc (20 mL×3). The combined organic layer waswashed with brine, dried over anhydrous Na₂SO₄, and concentrated invacuo. The crude product was purified by Prep-HPLC to afford Compound130 (20 mg, 18% yield). ¹H NMR (CDCl₃, 400 MHz) δ 7.62 (s, 1H), 7.53 (s,1H), 7.47-7.44 (m, 2H), 7.38 (t, J=7.6 Hz, 2H), 7.32 (d, J=8.4 Hz, 2H),7.22-7.18 (m, 4H), 6.20 (s, 1H), 6.12 (s, 1H), 3.99 (s, 3H).

Compound 158 was prepared following the similar procedure for obtainingCompound 117 using1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole inplace of XXV-9 as a white solid. ¹H NMR (CD₃OD, 400 MHz) δ 7.71 (m, 2H),7.61-7.58 (m, 2H), 7.55 (s, 1H), 7.48-7.46 (m, 2H), 6.83 (s, 1H), 3.88(s, 3H). MS (ESI) m/z [M+H]⁺ 380.1.

Compound 159 was prepared following the similar procedure for obtainingCompound 118 using propan-1-amine in place of benzyl amine as a whitesolid. ¹H NMR (400 MHz, CDCl₃) δ 7.52 (s, 1H), 7.46 (s, 1H), 7.35-7.32(m, 3H), 7.29-7.26 (m, 2H), 6.85 (t, J=4.8 Hz, 1H), 6.59 (s, 1H), 3.86(s, 3H), 3.22 (q, J=6.4 Hz, 2H), 1.45 (q, J=7.2 Hz, 2H), 0.82 (t, J=7.2Hz, 3H). MS (ESI) m/z [M+H]⁺ 420.1.

Compounds 136-140 were prepared from Compound 158 following the similarprocedure for obtaining Compound 103.

Compound 136: ¹H NMR (400 MHz, CDCl₃) δ 7.52 (s, 1H), 7.45-7.41 (m, 4H),7.32-7.29 (m, 2H), 7.17 (s, 1H), 6.71 (s, 1H), 4.18-4.14 (m, 2H), 3.98(s, 3H), 1.67-1.59 (m, 2H), 1.42-1.23 (m, 2H), 0.94 (t, J=7.2 Hz, 3H).MS (ESI) m/z [M+H]⁺ 450.1.

Compound 137: ¹H NMR (400 MHz, CDCl₃) δ 7.50 (s, 1H), 7.45 (s, 1H),7.43-7.41 (m, 3H), 7.29-7.27 (m, 2H), 7.16 (s, 1H), 6.72 (s, 1H),4.22-4.17 (m, 2H), 3.96 (s, 3H), 1.28-1.25 (m, 3H). MS (ESI) m/z [M+H]⁺422.1.

Compound 138: ¹H NMR (400 MHz, CDCl₃) δ 7.51 (s, 1H), 7.45-7.43 (m, 4H),7.33-7.30 (m, 2H), 7.18 (s, 1H), 6.75 (s, 1H), 3.98 (s, 3H), 3.77 (s,3H). MS (ESI) m/z [M+H]⁺ 408.1

Compound 139: ¹H NMR (400 MHz, CDCl₃) δ 7.52 (s, 1H), 7.47-7.43 (m, 4H),7.33-7.30 (m, 2H), 7.17 (s, 1H), 6.65 (s, 1H), 5.05-5.00 (m, 1H), 3.98(s, 3H), 1.28 (d, J=6.0 Hz, 3H). MS (ESI) m/z [M+H]⁺ 436.1.

Compound 140: ¹H NMR (CDCl₃, 400 MHz) δ 7.49 (s, 2H), 7.44-7.40 (m, 3H),7.38 (m, 5H), 7.33-7.30 (m, 2H), 7.29 (s, 1H), 7.16 (s, 1H), 6.77 (s,1H), 5.18 (s, 2H), 3.95 (s, 3H). MS (ESI) m/z [M+H]⁺ 484.14.

Compound 141: Compound 124 (150 mg, 0.43 mmol) was dissolved in 6 mL ofDCM/pyridine (v/v=1/1), and then acetyl chloride (36 mg, 0.46 mmol) wasadded. The mixture was stirred at rt overnight. Then the mixture wasdiluted with DCM (50 mL), washed with water and brine, dried overNa₂SO₄, concentrated in vacuo to give the crude product. The crudeproduct was purification by prep-TLC (PE/EA=1/1) to afford Compound 141(70 mg, 42% yield). ¹H NMR (CDCl₃, 400 MHz) δ 7.73 (s, 1H), 7.54 (s,1H), 7.45-7.43 (m, 3H), 7.32-7.30 (m, 2H), 7.22-7.19 (m, 2H), 3.99 (s,3H), 2.12 (s, 3H). MS (ESI) m/z (M+H)⁺ 392.9.

Compound 142 was prepared following the similar procedure for obtainingCompound 141 using bezoyl chloride in place of acetyl chloride. ¹H NMR(CDCl₃, 400 MHz) δ 8.07 (s, 1H), 7.94 (s, 1H), 7.68-7.64 (m, 3H),7.58-7.55 (m, 1H), 7.49-7.44 (m, 5H), 7.34-7.32 (m, 2H), 7.25 (s, 1H),4.00 (s, 3H). MS (ESI) m/z (M+H)⁺ 455.

Compound 143 was prepared from Compound 121 following the similarprocedure for obtaining Compound 91. ¹H NMR (CD₃OD, 400 MHz) δ 7.83 (s,2H), 7.73 (s, 1H), 7.56 (d, J=6.4 Hz, 2H), 7.54-7.37 (m, 7H), 6.20 (s,1H), 5.27 (s, 2H), 3.84 (s, 3H). MS (ESI) m/z (M+H)⁺ 442.1.

Compounds 144-152 were prepared by reacting Compound 121 with therelevant alcohol (1 eq.) in DMF and NAH (1.5 eq.) at rt for 2 hrs. Afterthe reaction mixture was quenched with water and extract with EA, theorganic phase was washed with brine, dried over Na₂SO₄ and concentratedin vacuo. The residue was purification by prep-TLC to give the finalproduct.

Compound 144: ¹H NMR (DMSO-d₆, 400 MHz) δ 7.94 (s, 1H), 7.87 (s, 1H),7.78 (s, 1H), 7.58 (d, J=8.8 Hz, 2H), 7.50 (d, J=8.8 Hz, 2H), 5.99 (s,1H), 4.20-4.18 (m, 2H), 3.80 (s, 3H), 3.75-3.73 (m, 2H), 3.35 (s, 3H).

Compound 145: ¹H NMR (DMSO-d₆, 400 MHz) δ 7.80 (s, 1H), 7.63 (s, 1H),7.46-7.44 (m, 2H), 7.38 (s, 1H), 7.33-7.26 (m, 2H), 6.05 (s, 1H), 4.18(m, 2H), 3.91 (s, 3H), 2.97-3.00 (m, 2H), 2.62 (m, 4H), 1.82 (m, 4H).

Compound 146: ¹H NMR (DMSO-d₆, 400 MHz) δ 7.80 (s, 1H), 7.55 (s, 1H),7.42-7.46 (m, 3H), 7.33-7.35 (m, 2H), 6.04 (s, 1H), 4.15 (t, J=5.2 Hz,2H), 3.95 (s, 3H), 3.83 (t, J=5.2 Hz, 2H), 3.39 (t, J=6.8 Hz, 2H), 2.36(t, J=8.0 Hz, 2H), 2.05-1.98 (m, 2H).

Compound 147: ¹H NMR (CDCl₃, 400 MHz) δ 7.80 (s, 1H), 7.67 (s, 1H),7.45-7.43 (m, 2H), 7.39 (s, 1H), 7.33-7.26 (m, 2H), 6.05 (s, 1H), 4.16(t, J=5.2 Hz, 2H), 3.92 (s, 3H), 3.74 (m, 4H), 2.85 (t, J=5.2 Hz, 2H),2.56 (m, 4H).

Compound 148: ¹H NMR (CDCl₃, 400 MHz) δ 7.65 (s, 1H), 7.56 (s, 1H),7.46-7.44 (m, 2H), 7.36-7.34 (m, 3H), 6.05 (s, 1H), 4.17-4.14 (m, 2H),3.93 (s, 3H), 3.11-3.03 (m, 10H). MS (ESI) m/z (M+H)⁺ 513.1.

Compound 149: ¹H NMR (CDCl₃, 400 MHz) δ 7.55 (s, 1H), 7.43 (m, 3H), 7.35(m, 3H), 6.06 (s, 1H), 4.73 (m, 1H), 3.95 (s, 3H), 3.21-3.14 (m, 2H),3.03-2.09 (m, 2H), 2.59-2.45 (m, 4H).

Compound 150: ¹H NMR (CDCl₃, 400 MHz) δ 7.69 (s, 1H), 7.56 (s, 1H),7.46-7.44 (m, 2H), 7.38-7.33 (m, 3H), 6.05 (s, 1H), 4.24-4.21 (m, 2H),4.16 (s, 2H), 3.93-3.91 (m, 5H), 3.84-3.81 (m, 2H), 3.39-3.37 (m, 2H).MS (ESI) m/z (M+H)⁺ 479.1.

Compound 151: ¹H NMR (CDCl₃, 400 MHz) δ 7.59 (s, 1H), 7.54 (s, 1H),7.46-7.43 (m, 2H), 7.37-7.34 (m, 3H), 6.06 (s, 1H), 4.61-4.58 (m, 1H),3.94 (s, 3H), 2.90 (m, 2H), 2.55 (m, 3H), 2.18-2.08 (m, 2H), 1.80-1.67(m, 2H). MS (ESI) m/z (M+H)⁺ 449.0.

Compound 152: ¹H NMR (CDCl₃, 400 MHz) δ 7.82 (s, 1H), 7.65 (s, 1H),7.46-7.44 (m, 2H), 7.40 (s, 1H), 7.39-7.32 (m, 2H), 6.04 (s, 1H), 4.16(t, J=5.6 Hz, 2H), 3.95 (s, 3H), 2.87 (t, J=5.6 Hz, 2H), 2.61-2.49 (m,8H), 2.31 (s, 3H).

Compound 153: Compound 122 (1.5 g, 4.06 mmol), phenol (763 mg, 8.12mmol) and K₃PO₄ (2.6 g, 12.2 mmol) were added into DMF (15 mL). Thesolution was degassed by N₂ for three times and then Pd₂(dba)₃ (570 mg,0.81 mmol) was added. The reaction mixture was stirred at 110° C. for 14hrs under N₂. After being cooled to rt, the mixture was diluted with EA(80 mL) and filtered; the filterate was washed with brine. The separatedorganic phase was dried over Na₂SO₄, concentrated under reducedpressure. The residue was purified by flash column chromatography(PE/EA=1/1) to give Compound 153 (848 mg, 49% yield). ¹H NMR (CDCl₃, 400MHz) δ 7.76 (s, 1H), 7.69 (s, 1H), 7.50-7.44 (m, 5H), 7.36-7.26 (m, 3H),7.16 (m, 2H), 5.79 (s, 1H), 3.94 (s, 3H). MS (ESI) m/z (M+H)⁺ 428.

Compound 156 was prepared following the similar procedure for obtainingCompound 153 using 3-chloro-5-hydroxybenzonitrile in place of phenol. ¹HNMR (CDCl₃, 400 MHz) δ 7.64-7.59 (m, 3H), 7.52 (s, 1H), 7.48-7.44 (m,3H), 7.39-7.36 (m, 3H), 5.82 (s, 1H), 3.94 (s, 3H). MS (ESI) m/z (M+H)⁺486.9.

To a stirred mixture of Compound 117 (350 mg, 0.89 mmol) in 10 mL of DCMwas added oxalyl chloride (335 mg, 2.63 mmol) at 0° C. The mixture wasstirred for 2 hrs, and then the mixture was concentrated under reducedpressure. The residue was re-dissolved in DCM (10 mL) and the mixturewas added to the well-stirred ammonia (5 mL) at 0° C. After the mixturewas stirred at 0° C. for 30 min, the reaction mixture was extracted withEA (20 mL×3). The combined organic layer was washed with brine, driedover anhydrous Na₂SO₄ and concentrated. The residue was purified bycolumn chromatography (CH₂Cl₂/MeOH=20/1) to give XXV-11 (220 mg, 63%yield). MS (ESI) m/z (M+H)⁺ 393.1.

To a solution of XXV-11 (220 mg, 0.56 mmol) in 10 mL of DCM was addedTEA (85.3 mg, 0.84 mmol) and TFAA (81.6 mg, 0.84 mmol). The reactionmixture was stirred at rt under N₂ for 3 hrs and then diluted with DCM(30 mL) and filtered. The filtrate was washed with brine, dried overNa₂SO₄, the residue was purified by prep-HPLC to give Compound 401 (180mg, 86% yield). ¹H NMR (CDCl₃, 400 MHz) δ 7.48-7.37 (m, 7H), 7.19-7.14(m, 3H). MS (ESI) m/z (M+H)⁺ 375.1.

Compound 402 was prepared following the similar procedure for obtainingCompound 401 using Compound 158 in place of Compound 117. ¹H NMR (CDCl₃,400 MHz) δ 7.83 (s, 1H), 7.76 (d, J=9.6 Hz, 1H), 7.61 (s, 3H), 7.39 (m,2H), 7.12 (d, J=9.6 Hz, 1H), 3.97 (s, 3H). MS (ESI) m/z (M+H)⁺ 361.1.

Compound 403 was prepared following the similar procedure for obtainingCompound 153 using4-chloro-1-(4-ethoxy-2-methylphenyl)-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2(1H)-onein place of Compound 122. ¹H NMR (CDCl₃, 400 MHz) δ 7.74 (s, 1H), 7.67(s, 1H), 7.47-7.43 (m, 2H), 7.39 (s, 1H), 7.30 (d, J=3.6 Hz, 1H), 7.17(d, J=3.6 Hz, 2H), 7.12 (d, J=3.6 Hz, 2H), 6.85-6.80 (m, 2H), 5.80 (s,1H), 4.04 (q, J=7.2 Hz, 2H), 3.92 (s, 3H), 2.15 (s, 3H), 1.32 (t, J=6.8Hz, 3H). MS (ESI) m/z (M+H)⁺ 402.2.

A mixture of Compound 122 in the relevant amine (1 mmol/1 mL) wasstirred at 160° C. for 4 hrs. After being cooled to rt, the mixture wasdiluted with H₂O, extracted with EtOAc, the organic layer was washedwith water and brine, dried over anhydrous Na₂SO₄, and concentrated invacuo, the crude product was purified by column chromatography(PE/EtOAc=1/1) to give the final products.

Alternatively, a solution of Compound 122 (1.355 mmol) in toluene (20mL) were added the relevant amine (2.71 mmol), NaOtBu (520 mg, 5.42mmol), Xphos (64.9 mg, 0.136 mmol), Pd(OAc)₂ (30.5 mg, 0.136 mmol). Themixture was degassed under in vacuum and purged with N₂ three times. Thereaction mixture was heated to 100° C. or to reflux overnight. Themixture was cooled to rt, diluted with water, extracted with EA. Thecombined organic layer was dried over Na₂SO₄, concentrated in vacuum.The residual was purified by silica gel chromatography eluted withDCM:MeOH (50:1-10:1) to give the final product.

Compounds 404-407, 411, 526-531, and 546-549 were prepared following thegeneral scheme as illustrated above.

Compound 404: ¹H NMR (CDCl₃, 400 MHz) δ 7.50 (s, 1H), 7.43-7.39 (m, 3H),7.30-7.25 (m, 3H), 7.06 (s, 1H), 6.88-6.80 (m, 2H), 5.64 (s, 1H), 4.85(t, J=6.0 Hz, 1H), 4.34 (d, J=6.0 Hz, 2H), 3.93 (s, 3H). MS (ESI) m/z(M+H)⁺ 477.1.

Compound 405: ¹H NMR (CDCl₃, 400 MHz) δ 7.54 (s, 1H), 7.45-7.40 (m, 4H),7.30-7.24 (m, 4H), 7.08 (s, 1H), 5.59 (s, 1H), 4.92 (t, J=6.0 Hz, 1H),4.38 (d, J=6.0 Hz, 2H), 3.95 (s, 3H). MS (ESI) m/z (M+H)⁺ 510.1.

Compound 406: ¹H NMR (CDCl₃, 400 MHz) δ 7.52 (s, 1H), 7.47-7.40 (m, 3H),7.35-7.20 (m, 5H), 7.11 (s, 1H), 5.91 (s, 1H), 4.97 (t, J=6.0 Hz, 1H),4.34 (d, J=6.0 Hz, 2H), 3.95 (s, 3H). MS (ESI) m/z (M+H)⁺ 475.1.

Compound 407: ¹H NMR (CDCl₃, 400 MHz) δ 7.52 (s, 1H), 7.46-7.41 (m, 3H),7.32-7.25 (m, 4H), 7.08-7.03 (m, 3H), 5.65 (s, 1H), 4.77 (t, J=5.6 Hz,1H), 4.30 (d, J=5.6 Hz, 2H), 3.94 (s, 3H). MS (ESI) m/z (M+H)⁺ 458.9.

Compound 411: ¹H NMR (CDCl₃, 400 MHz) δ 8.62 (s, 1H), 8.53 (s, 2H), 7.60(s, 1H), 7.50 (s, 1H), 7.45-7.43 (m, 2H), 7.31-7.29 (m, 2H), 7.12 (s,1H), 5.74 (t, J=5.2 Hz, 1H), 5.68 (s, 1H), 4.52 (d, J=5.2 Hz, 2H), 3.98(s, 3H). MS (ESI) m/z (M+H)⁺ 443.0.

Compound 526: ¹H NMR (CDCl₃, 300 MHz) δ 7.58 (d, J=8.1 Hz, 2H), 7.48 (s,1H), 7.33-7.38 (m, 5H), 6.59 (s, 1H), 7.21 (d, J=8.1 Hz, 2H), 7.03 (s,1H), 5.48 (s, 1H), 4.87 (t, J=5.7 Hz, 1H), 4.36 (d, J=5.7 Hz, 2H), 3.89(s, 3H).

Compound 527: ¹H NMR (Methanol-d₄, 300 MHz) δ 7.75 (s, 1H), 7.55 (d,J=5.7 Hz, 2H), 7.50-7.41 (m, 5H), 7.34 (d, J=8.7 Hz, 2H), 5.52 (s, 1H),4.51 (s, 2H), 3.86 (s, 3H).

Compound 528: ¹H NMR (DMSO-d₆, 400 MHz) δ 7.89 (s, 1H), 7.57 (s, 1H),7.52 (d, J=8.4 Hz, 2H), 7.44 (d, J=8.4 Hz, 2H), 7.40 (s, 1H), 7.25 (t,J=8.8 Hz, 1H), 6.80-6.83 (dd, J₁=2.4 Hz, J₂=12.4 Hz), 6.74-6.77 (dd,J₁=2.4 Hz, J₂=8.8 Hz), 6.63 (t, J=5.6 Hz, 1H), 5.35 (s, 1H), 4.32 (d,J=5.6 Hz, 2H), 4.00 (q, J=6.8 Hz, 2H), 3.86 (s, 3H), 1.29 (t, J=6.8 Hz,3H).

Compound 529: ¹H NMR (CDCl₃, 300 MHz) δ 8.65 (d, J=5.1 Hz, 2H), 7.58 (s,1H), 7.47 (s, 1H), 7.35-7.40 (m, 3H), 7.16-7.24 (m, 2H), 7.05 (s, 1H),6.10 (t, J=4.5 Hz, 1H), 5.65 (s, 1H), 4.50 (d, J=4.5 Hz, 2H), 3.92 (s,3H).

Compound 530: MS (ESI) m/z [M+H]⁺ 485.0. Hydrogen chloride salt: ¹H NMR(CDCl₃, 400 MHz) δ 7.91 (s, H), 7.58 (s, H), 7.54-7.50 (m, 2H),7.48-7.43 (m, 2H), 7.33 (m, 1H), 7.26 (d, J.=8.4 Hz, 2H), 6.89 (d,J.=8.4 Hz, 2H), 6.51 (m, 1H), 5.27 (s, 1H), 4.28 (d, J.=6.0 Hz, 2H),3.99 (q, J.=6.8 Hz, 2H), 3.88 (s, 3H), 1.31 (t, J.=7.2 Hz, 3H)

Compound 531: ¹H NMR (CDCl₃, 300 MHz) δ 9.11 (s, 1H), 8.62 (s, 2H), 7.46(s, 1H), 7.35 (d, J=9.3 Hz, 3H), 7.24 (s, 1H), 7.20 (d, J=4.2 Hz, 1H),7.03 (s, 1H), 5.53 (s, 1H), 4.80 (t, J=5.7 Hz, 1H), 4.34 (d, J=5.7 Hz,2H), 3.88 (s, 3H). MS (ESI) m/z [M+H]⁺ 443.0.

Preparation of various salts of Compound 531: Compound 531 was dissolvedin MeOH, followed by addition of aqueous salt solution. The mixture wasstirred at rt for 1 h. The reaction mixture was concentrated to dryness.The residual aqueous solution was lyophilized to give the finalcorresponding salt of Compound 531.

Hydrogen chloride salt: ¹H NMR (DMSO-d₆, 400 MHz) δ 9.10 (s, 1H), 8.82(s, 2H), 7.95 (s, 1H), 7.60 (s, 1H), 7.52 (d, J=9.2 Hz, 2H), 7.43 (d,J=8.4 Hz, 2H), 7.40 (s, 1H), 6.80 (t, J=5.6 Hz, 1H), 5.43 (s, 1H), 4.45(d, J=5.6 Hz, 1H), 3.87 (s, 3H).

Citrate salt: ¹H NMR (DMSO-d₆, 400 MHz) δ 12.22 (brs, 1H), 9.08 (s, 1H),9.08 (s, 1H), 8.80 (s, 1H), 7.91 (s, 1H), 7.58 (s, 1H), 7.49 (d, J=8.8Hz, 2H), 7.41 (d, J=8.8 Hz, 2H), 7.31 (s, 1H), 6.56 (t, J=6 Hz, 1H),5.28 (s, 1H), 4.41 (d, J=6 Hz, 2H), 3.86 (s, 3H), 2.74 (d, J=15.6 Hz,2H), 2.65 (d, J=15.6 Hz, 2H).

p-TsOH salt: ¹H NMR (DMSO-d₆, 400 MHz) δ 9.11 (s, 1H), 8.82 (s, 2H),7.97 (s, 1H), 7.61 (s, 1H), 7.45-7.56 (m, 7H), 7.10 (d, J=8 Hz, 2H),6.94 (s, 1H), 5.48 (s, 1H), 4.47 (d, J=5.2 Hz, 2H), 3.87 (s, 3H), 2.27(s, 3H).

Acetic acid salt: ¹H NMR (DMSO-d₆, 400 MHz) δ 9.18 (s, 1H), 8.70 (s,2H), 7.53 (s, 1H), 7.44 (s, 1H), 7.42 (d, J=8.8 Hz, 2H), 7.29 (d, J=8.8Hz, 2H), 7.10 (s, 1H), 4.87 (t, J=5.6 Hz, 1H), 4.41 (d, J=5.6 Hz, 2H),3.95 (s, 3H), 2.06 (s, 1H).

Compounds 546-549 were prepared by reacting4-bromo-1-(4-(trifluoromethoxy)phenyl)pyridin-2(1H)-one with thecorresponding amines.

Compound 546: ¹H NMR (DMSO-d₆, 300 MHz) δ 8.83 (d, J=5.1 Hz, 2H),7.49-7.44 (m, 6H), 7.37 (d, J=7.5 Hz, 1H), 6.01 (dd, J=1.8, 7.5 Hz, 1H),5.17 (s, 1H), 4.49 (d, J=5.7 Hz, 2H).

Compound 547: ¹H NMR (DMSO-d₆, 300 MHz) δ 8.55 (d, J=4.2 Hz, 1H), 7.82(d, J=7.5 Hz, 1H), 7.66 (d, J=5.1 Hz, 1H), 7.44-7.43 (m, 7H), 6.02 (t,J=7.5 Hz, 1H), 5.14 (s, 1H), 4.38 (d, J=5.7 Hz, 2H).

Compound 548: ¹H NMR (DMSO-d₆, 300 MHz) δ 9.12 (s, 1H), 8.80 (s, 2H),7.45-7.37 (m, 6H), 6.90 (t, J=7.5 Hz, 1H), 5.30 (s, 1H), 4.39 (d, J=5.7Hz, 2H).

Compound 549: ¹H NMR (DMSO-d₆, 300 MHz) δ 8.68-8.63 (m, 2H), 8.58 (s,1H), 7.51-7.36 (m, 6H), 5.98 (d, J=7.5 Hz, 1H), 5.23 (s, 1H), 4.48 (d,J=5.1 Hz, 2H).

Compound 538 was prepared from Compound 403 in three steps: first,Compound 403 (3.6 g, 11 mmol) was stirred in HBr aqueous solution (40%,30 mL) at 90° C. for 12 hrs. After standard workup, the resultingintermediate was redissolved in POCl₃ (20 mL) and refluxed for 2 h toafford the corresponding chloride (520 mg, 18% yield). Subsequently,acetone (10 mL), K₂CO₃ (342 mg, 2.48 mmol) and iodomethane (387 mg, 2.48mmol) were added in portions. The mixture was stirred at 60° C.overnight. The mixture was cooled to rt and filtered. The filtrate wasconcentrated and purified by flash column chromatography (PE:EA=2:1) togive Compound 538 (252 mg, 43%). ¹H NMR (DMSO-d₆, 400 MHz) δ 7.96 (s,1H), 7.69 (s, 1H), 7.64 (s, 1H), 7.18-7.16 (d, J=8 Hz, 1H), 6.92 (s,1H), 6.85-6.83 (m, 1H), 6.76 (s, 1H), 4.05 (q, J=6.8 Hz, 2H), 3.82 (s,3H), 2.01 (s, 3H), 1.33 (t, J=6.8 Hz, 3H). MS (ESI) m/z (M+H)⁺ 344.1.

Compound 543: Compound 538 (100 mg, 0.29 mmol) was dissolved in BnNH₂ (5mL), the mixture was stirred at 160° C. for 3 h under N₂. After cooledto rt, the mixture was diluted with water and extracted with EtOAc.Following standard workup and purification, Compound 543 was obtained(53 mg, yield 44%). MS (ESI) m/z (M+H)⁺ 414.9.

Alternative way to prepare Compound 543: first,5-bromo-4-chloro-2-methoxypyridine was reacted with1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleunder the standard Suzuki-Coupling condition to form4-chloro-2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridine; then it wassubject to HBr hydrolysis, followed by a second Suzuki-Coupling with(4-ethoxy-2-methylphenyl)boronic acid, then reaction with BnNH₂ asdescribed herein. Hydrogen chloride salt: ¹H NMR (DMSO-d₆, 400 MHz)¹HNMR (DMSO-d₆, 400 MHz) δ 8.01 (s, 1H), 7.64 (s, 1H), 7.46 (s, 1H),7.41-7.35 (m, 5H), 7.28 (m, 1H), 7.18 (d, J=8.8 Hz, 1H), 6.93 (s, 1H),6.83 (d, J=8.8 Hz, 1H), 5.87 (s, 1H), 4.45 (s, 2H), 4.04 (q, J=6.8 Hz,2H), 3.89 (s, 3H), 2.00 (s, 3H), 1.32 (t, J=6.8 Hz, 3H).

Compounds 699-704 and 706 were prepared by reacting4-chloro-1-(4-ethoxy-2-methylphenyl)-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2(1H)-onewith the corresponding amines following the similar procedure describedabove. The HCl salts thereof were also prepared following the similarprocedure above.

Compound 699: ¹H NMR (DMSO-d₆, 400 MHz) δ 8.54 (d, J=4.0 Hz, 1H), 7.90(s, 1H), 7.80 (dt, J=1.8, 7.7 Hz, 1H), 7.58 (s, 1H), 7.40 (d, J=7.8 Hz,1H), 7.29 (dd, J₁=5.3, J₂=6.8 Hz, 1H), 7.08 (s, 1H), 7.04 (d, J=8.5 Hz,1H), 6.86 (d, J=2.8 Hz, 1H), 6.78 (dd, J₁=2.9, J₂=8.7 Hz, 1H), 6.49 (t,J=5.5 Hz, 1H), 5.75 (s, 1H), 5.22 (s, 1H), 4.42 (d, J=5.5 Hz, 2H), 4.03(q, J=6.9 Hz, 2H), 3.87 (s, 3H), 2.00 (s, 3H), 1.32 (t, J=7.0 Hz, 3H).MS (ESI) m/z (M+H)⁺ 416.2.

HCl salt of Compound 699: ¹H NMR (DMSO-d₆, 400 MHz) δ 8.74 (d, J=4.5 Hz,1H), 8.23 (t, J=7.2 Hz, 1H), 7.99 (s, 1H), 7.77 (d, J=8.0 Hz, 1H),7.71-7.65 (m, 1H), 7.64 (d, J=0.8 Hz, 1H), 7.25 (s, 1H), 7.08 (d, J=8.5Hz, 1H), 6.88 (d, J=2.8 Hz, 1H), 6.85-6.77 (m, 2H), 5.46 (s, 1H), 4.65(d, J=4.5 Hz, 2H), 4.07-4.01 (m, 2H), 3.88 (s, 3H), 2.00 (s, 3H), 1.32(t, J=6.9 Hz, 3H). MS (ESI) m/z (M+H)⁺ 416.2.

Compound 700: ¹H NMR (DMSO-d₆, 400 MHz) δ 8.56-8.50 (m, 2H), 7.91 (s,1H), 7.58 (s, 1H), 7.37 (d, J=5.8 Hz, 2H), 7.08-7.01 (m, 2H), 6.85 (d,J=2.5 Hz, 1H), 6.77 (dd, J₁=2.8, J₂=8.5 Hz, 1H), 6.46 (t, J=6.1 Hz, 1H),5.75 (s, 1H), 5.09 (s, 1H), 4.38 (d, J=6.0 Hz, 2H), 4.02 (q, J=6.9 Hz,2H), 3.87 (s, 3H), 1.99 (s, 3H), 1.32 (t, J=6.9 Hz, 3H). MS (ESI) m/z(M+H)⁺416.2.

HCl salt of Compound 700: ¹H NMR (DMSO-d₆, 400 MHz) δ 8.85 (d, J=6.5 Hz,2H), 7.98 (d, J=6.3 Hz, 2H), 7.96 (s, 1H), 7.63 (s, 1H), 7.17 (s, 1H),7.04 (d, J=8.8 Hz, 1H), 6.86 (d, J=2.8 Hz, 1H), 6.78 (dd, J₁=2.8, J₂=8.5Hz, 1H), 6.73 (t, J=6.1 Hz, 1H), 5.20 (s, 1H), 4.66 (d, J=6.0 Hz, 2H),4.03 (d, J=7.0 Hz, 2H), 3.88 (s, 3H), 2.00-1.98 (m, 3H), 1.32 (t, J=6.9Hz, 3H). MS (ESI) m/z (M+H)⁺ 416.2.

Compound 701: ¹H NMR (DMSO-d₆, 400 MHz) δ 8.59 (d, J=1.8 Hz, 1H), 8.47(dd, J₁=1.6, J₂=4.9 Hz, 1H), 7.89 (s, 1H), 7.77 (d, J=7.8 Hz, 1H), 7.56(s, 1H), 7.38 (dd, J₁=4.8, J₂=7.8 Hz, 1H), 7.06-7.01 (m, 2H), 6.85 (d,J=2.5 Hz, 1H), 6.77 (dd, J₁=2.8, J₂=8.5 Hz, 1H), 6.42 (t, J=6.1 Hz, 1H),5.75 (s, 1H), 5.20 (s, 1H), 4.38 (d, J=6.0 Hz, 2H), 4.02 (q, J=7.0 Hz,2H), 3.86 (s, 3H), 1.99 (s, 3H), 1.32 (t, J=7.0 Hz, 3H). MS (ESI) m/z(M+H)⁺ 416.2.

HCl salt of Compound 701: ¹H NMR (DMSO-d₆, 400 MHz) δ 8.90 (s, 1H), 8.78(d, J=5.3 Hz, 1H), 8.46 (d, J=8.0 Hz, 1H), 8.00-7.91 (m, 2H), 7.61 (s,1H), 7.17 (s, 1H), 7.05 (d, J=8.5 Hz, 1H), 6.87 (d, J=2.5 Hz, 1H), 6.78(dd, J₁=2.5, J₂=8.5 Hz, 1H), 6.74 (t, J=6.0 Hz, 1H), 5.39 (s, 1H), 4.56(d, J=5.8 Hz, 2H), 4.06-4.01 (m, 2H), 3.87 (s, 3H), 1.99 (s, 3H), 1.32(t, J=6.9 Hz, 3H). MS (ESI) m/z (M+H)⁺ 416.2.

Compound 702: ¹H NMR (DMSO-d₆, 400 MHz) δ 7.87 (s., 1H), 7.55 (s, 1H),7.45-7.40 (m, 1H), 7.30-7.20 (m, 1H), 7.10-7.02 (m, 3H), 6.85 (d, J=2.4Hz, 1H), 6.79-6.76 (m, 1H), 6.35-6.31 (m, 1H), 5.18 (s, 1H), 4.35 (d,J=5.6 Hz, 2H), 4.02 (q, J=7.2 Hz, 2H), 3.86 (s, 3H), 2.00 (s, 3H), 1.32(t, J=7.2 Hz, 3H).

HCl salt of Compound 702: ¹H NMR (DMSO-d₆, 400 MHz) δ 7.91 (s, 1H), 7.58(s, 1H), 7.47-7.43 (m, 1H), 7.30-7.24 (m, 2H), 7.10 (d, J=8.4 Hz, 2H),6.88 (s., 1H), 6.81 (d, J=8.4 Hz, 1H), 6.73 (s, 1H), 5.42 (s, 1H), 4.39(d, J=4.8 Hz, 2H), 4.03 (q, J=6.8 Hz, 2H), 3.87 (s, 3H), 2.00 (s, 3H),1.32 (t, J=6.8 Hz, 3H).

Compound 703: ¹H NMR (DMSO-d₆, 400 MHz) δ 7.92 (s., 1H), 7.57 (s, 1H),7.12-7.03 (m, 5H), 6.85 (d, J=2.4 Hz, 1H), 6.78 (d, J=2.4 Hz, 1H), 6.46(t, J=6.0 Hz, 1H), 5.15 (s, 1H), 4.36 (d, J=6.0 Hz, 2H), 4.02 (q, J=7.2Hz, 2H), 3.87 (s, 3H), 2.00 (s, 3H), 1.32 (t, J=7.2 Hz, 3H).

HCl salt of Compound 703: ¹H NMR (DMSO-d₆, 400 MHz) δ 7.98 (s, 1H), 7.61(s, 1H), 7.26 (s, 1H), 7.13-7.10 (m, 4H), 6.88 (brs, 2H), 6.80 (d, J=8.4Hz, 1H), 5.42 (s, 1H), 4.41 (d, J=4.8 Hz, 2H), 4.03 (q, J=6.8 Hz, 2H),3.88 (s, 3H), 2.0 (s, 3H), 1.32 (t, J=6.8 Hz, 3H).

Compound 704: ¹H NMR (DMSO-d₆, 400 MHz) δ 7.91 (s, 1H), 7.83 (d, J=8.0Hz, 2H), 7.61-7.52 (m, 3H), 7.06 (s, 1H), 7.03 (d, J=8.8 Hz, 1H), 6.85(d, J=2.8 Hz, 1H), 6.78 (dd, J=2.8, 8.4 Hz, 1H), 6.50 (t, J=6.0 Hz, 1H),5.76 (s, 1H), 5.10 (s, 1H), 4.44 (d, J=6.0 Hz, 2H), 4.03 (q, J=7.2 Hz,2H), 3.87 (s, 3H), 1.99 (s, 3H), 1.32 (t, J=7.2 Hz, 3H).

HCl salt of Compound 704: ¹H NMR (DMSO-d₆, 400 MHz) δ 7.95 (s, 1H), 7.83(d, J=8.0 Hz, 2H), 7.61 (s, 1H), 7.56 (d, J=8.0 Hz, 2H), 7.27 (s, 1H),7.09 (d, J=8.8 Hz, 1H), 6.99 (t, J=5.8 Hz, 1H), 6.87 (d, J=2.8 Hz, 1H),6.79 (dd, J=2.8, 8.8 Hz, 1H), 5.41 (s, 1H), 4.48 (d, J=5.6 Hz, 2H), 4.02(q, J=7.2 Hz, 2H), 3.87 (s, 3H), 1.98 (s, 3H), 1.31 (t, J=7.2 Hz, 3H).

Compound 705: ¹H NMR (DMSO-d₆, 400 MHz) δ 7.84 (s, 1H), 7.58 (s, 1H),7.33-7.21 (m, 4H), 7.16 (d, J=7.2 Hz, 2H), 7.16 (d, J=7.2 Hz, 1H), 7.07(s, 1H), 6.87 (d, J=2.8 Hz, 1H), 5.69 (s, 1H), 4.11 (d, J=8.8 Hz, 2H),4.02 (q, J=7.2 Hz, 2H), 3.75 (s, 3H), 2.52 (s, 3H), 2.00 (s, 3H), 1.31(t, J=7.2 Hz, 3H).

HCl salt of Compound 705: ¹H NMR (DMSO-d₆, 400 MHz) δ 7.87 (s, 1H), 7.60(s, 1H), 7.37-7.24 (m, 4H), 7.19 (d, J=7.0 Hz, 2H), 7.14 (d, J=8.8 Hz,1H), 6.91 (d, J=2.5 Hz, 1H), 6.83 (dd, J=2.8, 8.5 Hz, 1H), 5.83 (s, 1H),4.26-4.13 (m, 2H), 4.05 (q, J=7.0 Hz, 2H), 3.78 (s, 3H), 2.58 (s, 3H),2.03 (s, 3H), 1.34 (t, J=7.0 Hz, 3H).

Compound 706: ¹H NMR (DMSO-d₆, 400 MHz) δ 7.86 (s, 1H), 7.54 (s, 1H),7.41 (s, 1H), 7.12 (d, J=8.4 Hz, 1H), 7.05 (d, J=6.8 Hz, 1H), 6.86 (d,J=2.8 Hz, 1H), 6.80-6.72 (m, 3H), 5.97 (t, J=5.6 Hz, 1H), 5.15 (s, 1H),4.22 (d, J=5.2 Hz, 2H), 4.06-3.98 (m, 4H), 3.85 (s, 3H), 2.29 (s, 3H),2.01 (s, 3H), 1.35-1.29 (m, 6H).

HCl salt of Compound 706: ¹H NMR (DMSO-d₆, 400 MHz) δ 7.97 (s, 1H), 7.62(s, 1H), 7.41 (s, 1H), 7.16 (dd, J=8.5, 17.3 Hz, 2H), 6.98-6.90 (m, 2H),6.84 (dd, J=2.8, 8.5 Hz, 1H), 6.80 (s, 1H), 6.74 (dd, J=2.6, 8.4 Hz,1H), 5.66 (br. s., 1H), 4.31 (d, J=5.3 Hz, 2H), 4.10-3.91 (m, 4H), 3.88(s, 3H), 2.32 (s, 3H), 2.02 (s, 3H), 1.35-1.29 (m, 6H).

Compound 707: ¹H NMR (DMSO-d₆, 400 MHz) δ 7.85 (s, 1H), 7.53 (s, 1H),7.26 (d, J=8.4 Hz, 2H), 7.01 (t, J=2.4 Hz, 2H), 6.90 (d, J=8.8 Hz, 2H),6.83 (d, J=2.8 Hz, 1H), 6.76 (t, J=5.6 Hz, 1H), 5.18 (s, 1H), 4.24 (d,J=5.6 Hz, 2H), 4.06-4.00 (m, 4H), 3.84 (s, 3H), 3.63 (t, J=4.8, 2H),3.29 (s, 3H), 1.97 (s, 3H), 1.31 (t, J=6.8 Hz, 3H).

HCl salt of Compound 707: ¹H NMR (DMSO-d₆, 400 MHz) δ 7.97 (s, 1H), 7.61(s, 1H), 7.36 (d, J=2.5 Hz, 1H), 7.31 (d, J=8.5 Hz, 2H), 7.18-7.06 (m,2H), 6.96-6.89 (m, 3H), 6.84-6.81 (m, 1H), 5.71 (brs, 1H), 4.34 (brs,2H), 4.09-4.02 (m, 4H), 3.89 (s, 3H), 3.66-3.64 (m, 2H), 3.30 (s, 3H),2.00 (s, 3H), 1.33 (t, J=7.0 Hz, 3H).

Compound 708 was prepared by HBr hydrolysis of2-methoxy-4,5-bis(1-methyl-1H-pyrazol-4-yl)pyridine, followed bystandard copper acetate/pyridine/pyridine-N-oxide catalyzed reaction inDMF at 90° C. to afford the final product. ¹H NMR (DMSO-d₆, 400 MHz) δ7.71 (s, 1H), 7.65-7.63 (m, 3H), 7.56 (s, 1H), 7.52 (d, J=8.0 Hz, 2H),7.33 (s, 1H), 7.28 (s, 1H), 6.60 (s, 1H), 3.82 (s, 3H), 3.81 (s, 3H).

Compound 122 (1 eq.), phenol (XXV-14, 2 eq.) and K₃PO₄ (3 eq.) wereadded into DMF. The solution was degassed by nitrogen for three timesand then Pd₂(dba)₃ (0.2 eq.) was added. The reaction mixture was stirredat 110° C. for 14 hrs under N₂. After being cooled to rt, the mixturewas diluted with EA and filtered; the filtrate was washed with brine.The separated organic phase was dried over Na₂SO₄, concentrated underreduced pressure. The residue was purified by column chromatography(PE/EA=1/1) to give the final product.

Compounds 408-410 and 412-414 were prepared following the general schemeas illustrated above.

Compound 408: ¹H NMR (CDCl₃, 400 MHz) δ 7.74 (s, 1H), 7.68 (s, 1H),7.49-7.45 (m, 3H), 7.37-7.33 (m, 2H), 7.30-7.22 (m, 4H), 5.79 (s, 1H),3.94 (s, 3H). MS (ESI) m/z (M+H)⁺ 446.1.

Compound 409: ¹H NMR (CDCl₃, 400 MHz) δ 7.70 (s, 1H), 7.67 (s, 1H), 7.50(s, 1H), 7.47-7.42 (m, 3H), 7.37-7.33 (m, 2H), 7.05-7.00 (m, 1H),6.98-6.96 (m, 1H), 6.94-6.90 (m, 1H), 5.84 (s, 1H), 3.94 (s, 3H). MS(ESI) m/z (M+H)⁺ 445.9.

Compound 410: ¹H NMR (CDCl₃, 400 MHz) δ 7.72 (s, 1H), 7.68 (s, 1H),7.49-7.44 (m, 3H), 7.36-7.34 (m, 2H), 7.17-7.14 (m, 4H), 5.76 (s, 1H),3.94 (s, 3H). MS (ESI) m/z (M+H)⁺ 445.9.

Compound 412: ¹H NMR (CDCl₃, 400 MHz) δ 7.70 (s, 1H), 7.67 (s, 1H),7.49-7.42 (m, 5H), 7.36-7.34 (m, 2H), 7.12-7.10 (m, 2H), 5.78 (s, 1H),3.94 (s, 3H). MS (ESI) m/z (M+H)⁺ 462.1.

Compound 413: ¹H NMR (CDCl₃, 400 MHz) δ 7.70 (s, 1H), 7.67 (s, 1H), 7.50(s, 1H), 7.47-7.35 (m, 5H), 7.32-7.29 (m, 1H), 7.20-7.19 (m, 1H),7.10-7.06 (m, 1H), 5.82 (s, 1H), 3.94 (s, 3H). MS (ESI) m/z (M+H)⁺462.1.

Compound 414: ¹H NMR (CDCl₃, 400 MHz) δ 7.83 (s, 1H), 7.79 (s, 1H),7.55-7.45 (m, 4H), 7.40-7.34 (m, 3H), 7.31-7.29 (m, 1H), 7.24-7.21 (m,1H), 5.74 (s, 1H), 3.97 (s, 3H). MS (ESI) m/z (M+H)⁺ 462.1.

Compounds 533 and 535 were prepared by reacting Compound 122 with thecorresponding substituted phenol in DMF and KOH at 130° C. overnight.

Compound 533: ¹HNMR (CDCl₃, 400 MHz) δ 7.75 (s, 1H), 7.68 (s, 1H),7.48-7.43 (m, 3H), 7.34 (d, J=8.4 Hz, 2H), 7.06 (d, J=9.2 Hz, 2H), 6.69(d, J=9.2 Hz, 2H), 5.78 (s, 1H), 4.15 (t, J=4.8 Hz, 1H), 3.94 (s, 3H),3.78 (t, J=4.8 Hz, 2H), 3.48 (s, 3H).

Compound 535: ¹H NMR (DMSO-d₆, 400 MHz) δ 8.05-8.01 (m, 5H), 7.84 (s,1H), 7.61 (d, J=8.8 Hz, 2H), 7.53 (d, J=8.4 Hz, 2H), 7.45 (s, 1H), 7.37(s, 1H), 7.35 (s, 1H), 5.46 (s, 1H), 3.84 (s, 3H). MS (ESI) m/z (M+H)⁺457.2.

Preparation of Compound 664: To a solution of Compound 122 (210 mg,0.569 mmol) in dioxane (20 mL) were added pyridazin-3-ylmethanaminehydrochloride (165 mg, 1.14 mmol), NaOtBu (218 mg, 2.28 mmol), Xphos(27.2 mg, 0.057 mmol), precatalyst 13 (44.8 mg, 0.057 mmol). The mixturewas degassed under in vacuum and purged with N₂ three times. Thereaction mixture was stirred at 100° C. for 14 h. The mixture was cooledto rt. The mixture was diluted with water and extracted with EA. Thecombined organic layer was dried over Na₂SO₄, concentrated in vacuum.The residue was purified by column chromatography on silica gel elutedwith DCM:MeOH (50:1-10:1) to give Compound 664 (50 mg, 20% yield) as apale yellow solid. ¹H NMR (DMSO-d₆, 400 MHz) δ 9.15 (s, 1H), 7.91 (s,1H), 7.67 (s, 2H), 7.60 (s, 1H), 7.49 (d, J=8.8 Hz, 2H), 7.42 (d, J=8.8Hz, 2H), 7.33 (s, 1H), 6.67 (t, 1H), 5.25 (s, 1H), 4.62 (t, J=5.6 Hz,1H), 3.87 (s, 3H).

Compound 696 was prepared by reacting4-chloro-1-(4-ethoxy-2-methylphenyl)-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2(1H)-onewith 2-isopropoxyethanol in the presence of NaH in DMF solution at rtfor 12 hrs to afford the final product as a yellow solid. ¹H NMR (CDCl₃,400 MHz) δ 7.78 (s, 1H), 7.66 (s, 1H), 7.32 (s, 1H), 7.15-7.12 (m, 1H),6.89-6.81 (m, 2H), 6.08 (s, 1H), 4.22-4.18 (m, 2H), 4.10-4.05 (q, J=6.9Hz, 2H), 3.93 (s, 3H), 3.87-3.85 (dd, J=3.6, 5.6 Hz, 2H), 3.77-3.74 (td,J=6.1, 12.2 Hz, 1H), 2.16 (s, 3H), 1.45 (t, J=6.9 Hz, 3H), 1.27 (d,J=6.3 Hz, 6H). MS (ESI) m/z (M+H⁺) 412.3.

Compound 697 was prepared by reacting4-chloro-1-(4-ethoxy-2-methylphenyl)-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2(1H)-onewith 2-(2-methoxyethoxy)ethanol in the presence of NaH in DMF solutionat rt for 12 hrs to afford the final product as a light yellow solid. ¹HNMR (CDCl₃, 400 MHz) δ 7.79 (s, 1H), 7.64 (s, 1H), 7.31 (s, 1H), 7.13(d, J=8.5 Hz, 1H), 6.89-6.81 (m, 2H), 6.07 (s, 1H), 4.25-4.20 (m, 2H),4.11-4.03 (q, J=6.9 Hz, 2H), 3.96-3.90 (m, 5H), 3.78-3.72 (m, 2H),3.66-3.60 (m, 2H), 3.45-3.40 (m, 3H), 2.16 (s, 3H), 1.45 (t, J=6.9 Hz,3H). MS (ESI) m/z (M+H⁺) 428.3.

Compound 698 was prepared by reacting4-chloro-1-(4-ethoxy-2-methylphenyl)-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2(1H)-onewith tetrahydro-2H-pyran-4-ol in the presence of NaH in DMF solution atrt for 16 hrs to afford the final product as a light yellow solid. ¹HNMR (CDCl₃, 400 MHz) δ 7.63 (s, 1H), 7.60 (s, 1H), 7.31 (s, 1H), 7.13(d, J=8.5 Hz, 1H), 6.89-6.81 (m, 2H), 6.10 (s, 1H), 4.64 (t t, J=3.9,8.0 Hz, 1H), 4.07 (q, J=6.9 Hz, 2H), 4.04-3.96 (m, 2H), 3.95 (s, 3H),3.64 (dt, J=1.8, 8.8 Hz, 2H), 2.21-2.12 (m, 5H), 1.91 (ttd, J=4.0, 8.4,12.8 Hz, 2H), 1.45 (t, J=7.0 Hz, 3H). MS (ESI) m/z (M+H⁺) 410.2.

Example 11-D Synthesis of Compound 154 (Scheme XXVI)

XXVI-1 (1.0 g, 6.67 mmol) and K₂CO₃ (1.38 g, 10 mmol) were added into inacetone (25 mL). And then EtI (1.14 g, 7.33 mmol) was added. The mixturewas heated to reflux for 24 hrs. The mixture was cooled to rt andremoved the solvent. Then the crude product was diluted with EA (100mL), washed with water and brine, dried over Na₂SO₄, concentrated invacuo to give XXVI-2 (870 mg, 73% yield), which was used directlywithout further purification.

A mixture of XXVI-2 (1.2 g, 6.74 mmol) and m-CPBA (1.5 g, 8.76 mmol) inDCM (30 mL) was refluxed for 48 hrs. The reaction mixture was cooled tort, diluted with DCM (100 mL), washed with saturated aq.Na₂S₂O₃ and aq.K₂CO₃, dried over Na₂SO₄. Concentrated in vacuo to give XXVI-3 (1.0 g,77% crude yield), which was used directly without further purification.

XXVI-3 (1 g, 5 mmol) was dissolved in ethanol (10 mL), then treated witha solution of NaOH (2.6 g) in H₂O (3 mL) slowly. The resultant mixturewas stirred at rt for 4 hrs. The resultant mixture was concentrated andresidue was diluted with water (10 mL). The mixture was made acidic withdiluted HCl (aq.) and extracted with EA (50 mL×3). The organic phaseswere combined, washed with brine, dried over Na₂SO₄, concentrated underreduced pressure to give the crude product. The residue was purificationby flash chromatography on silica gel (PE/EA=5:1→2:1) to give XXVI-4(800 mg, ˜100% yield).

Compound 154 was prepared by following the similar procedure describedin synthesis of Compound 153 (101 mg, 20% yield). ¹H NMR (CDCl₃, 400MHz) δ 7.76 (s, 1H), 7.68 (s, 1H), 7.47-7.44 (m, 3H), 7.36-7.34 (m, 2H),6.93-6.84 (m, 3H), 5.80 (s, 1H), 4.05 (q, J=7.2 Hz, 2H), 3.93 (s, 3H),2.24 (s, 3H), 1.46 (t, J=7.2 Hz, 3H). MS (ESI) m/z (M+H)⁺ 486.

Compound 155 was prepared by following the similar procedure forobtaining Compound 154 using 3-chloro-4-ethoxyphenol in place of XXVI-4.¹H NMR (CDCl₃, 400 MHz) δ 7.71 (s, 1H), 7.67 (s, 1H), 7.48-7.44 (m, 3H),7.36-7.34 (m, 2H), 7.21 (s, 1H), 7.03-6.96 (m, 2H), 5.80 (s, 1H), 4.14(q, J=7.2 Hz, 2H), 3.94 (s, 3H), 1.51 (t, J=7.2 Hz, 3H). MS (ESI) m/z(M+H)⁺505.9.

Compound 157 was prepared by following the similar procedure forobtaining Compound 154 using 2-ethoxy-5-hydroxybenzonitrile in place ofXXVI-4. ¹H NMR (CDCl₃, 400 MHz) δ 7.67 (d, J=7.6 Hz, 2H), 7.50-7.44 (m,3H), 7.39-7.31 (m, 4H), 7.03 (d, J=9.2 Hz, 1H), 5.73 (s, 1H), 4.19 (q,J=6.8 Hz, 2H), 3.94 (s, 3H), 1.52 (t, J=6.8 Hz, 3H). MS (ESI) m/z(M+H)⁺497.

Compound 162 was prepared following the similar procedure for obtainingCompound 85 using1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole inplace of XXIII-4 and using (4-ethoxy-2-methylphenyl)boronic acid inplace of XXIII-7. ¹H NMR (DMSO-d₆, 400 MHz) δ 7.93 (s, 1H), 7.71 (s,1H), 7.64 (s, 1H), 7.10 (d, J=8.0 Hz, 1H), 6.90 (d, J=2.8 Hz, 1H),6.84-6.81 (m, 1H), 5.95 (s, 1H), 4.04 (q, J=7.2 Hz, 2H), 3.86 (s, 3H),3.79 (s, 3H), 2.00 (s, 3H), 1.33 (t, J=7.2 Hz, 3H). MS (ESI) m/z (M+H)⁺340.1.

Compound 532 was prepared following the similar procedure for obtainingCompound 154 using4-chloro-1-(4-fluorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2(1H)-onein place of Compound 122 and using phenol in place of XXIV-4. ¹H NMR(CDCl₃, 400 MHz) δ 7.75 (s, 1H), 7.68 (s, 1H), 7.49-7.44 (m, 3H),7.39-7.36 (m, 2H), 7.32-7.20 (m, 1H), 7.18-7.14 (m, 4H), 5.79 (s, 1H),3.93 (s, 3H). MS (ESI) m/z [M+H]⁺ 362.1

Compound 534 was prepared following the similar procedure for thesynthesis of Compound 532. ¹H NMR (Methanol-d₄, 400 MHz) δ 8.02 (s, 1H),7.93 (s, 1H), 7.85 (s, 1H), 7.58-7.54 (m, 4H), 7.45 (d, J=8.8 Hz, 2H),7.41-7.37 (m, 1H), 7.27 (d, J=8.8 Hz, 2H), 5.67 (s, 1H), 3.93 (s, 3H).MS (ESI) m/z (M+H)⁺ 378.1.

Example 11-E Synthesis of Compound 542

To a mixture of compound 1 (68 g, 0.465 mol) in toluene (250 mL) wasadded CuI (17.9 g, 0.093 mol), (Me₂NHCH₂)₂ (36.8 g, 0.418 mol) and NaOMe(50.2 g 0.93 mol). The mixture was purged with nitrogen for three timesand then heated at 100° C. for 8 hours. The mixture was concentrated toremove toluene, diluted with H₂O and extracted with EtOAc. Afterstandard workup, the crude product was chromatographed on silica gel(PE) to give compound 2 (39.5 g, 60% yield).

To a solution of compound 2 (28.7 g. 0.2 mol) in DMF (50 mL) was addedNBS (35.5 g, 0.2 mol). The mixture was heated at 90° C. for 8 hours. Thecrude compound 3 was collected by filtration. (22 g, 50% yield).

To a stirred mixture of compound 3 (4 g, 18.1 mmol), compound 4 (4.52 g21.72 mmol), and K₂CO₃ (5 g, 36.2 mmol) in DME/H₂O (48 mL, v/v=5/1) wasadded Pd(dppf)Cl₂ (668 mg, 0.91 mmol) under N₂ protection. The reactionmixture was degassed with nitrogen again and refluxed overnight. Themixture was concentrated, diluted with H₂O and extracted with EtOAc. Thecombined organic layer was washed with brine, dried over anhydrousNa₂SO₄, and concentrated in vacuo. The residue was purified by columnchromatography (PE/EA=2/1) to give compound 5 (2.8 g, 69% yield) as apale yellow solid.

To a solution of compound 5 (500 mg, 2.24 mmol) in toluene (20 mL) wereadded compound 6 (757.1 mg, 4.48 mmol), NaOtBu (860.2 mg, 8.96 mmol),Xantphos (129.5 mg, 0.224 mmol), Pd(OAc)₂ (50.2 mg, 0.224 mmol). Themixture was degassed under in vacuum and purged with N₂ three times. Thereaction mixture was stirred at 100° C. for 14 h. The mixture was cooledto rt, diluted with water and extracted with EA. The combined organiclayer was dried over Na₂SO₄, concentrated in vacuum. The residue waspurified by silica gel chromatography eluted with DCM:MeOH (50:1-10:1)to afford compound 7 (300 mg, 45%) as a pale yellow solid.

Compound 7 (300 mg, 1.01 mmol) was dissolved in aq. HBr (40%, 15 mL),the mixture was heated to reflux overnight. After cooling to rt, themixture was adjusted with aq. NaOH (1 M) to pH=4-5, the resultingprecipitate was collected by filtration and dried in vacuo to giveCompound 542 (40 mg, 14% yield). ¹H NMR (DMSO-d₆, 400 MHz) δ 10.60 (s,1H), 8.81 (d, J=4.8 Hz, 2H), 7.85 (s, 1H), 7.55 (s, 1H), 7.43 (t, J=4.8Hz, 2H), 6.99 (s, 1H), 6.33 (t, J=5.2 Hz, 1H), 5.16 (s, 1H), 4.47 (d,J=5.2 Hz, 1H), 3.89 (s, 3H).

Compound 544 was prepared following the similar procedure for thesynthesis of Compound 542 using pyridin-2-ylmethanamine in place ofcompound 6. ¹H NMR (DMSO-d₆, 400 MHz) δ 10.56 (s, 1H), 8.52-8.51 (m,1H), 7.85 (s, 1H), 7.90-7.56 (m, 1H), 7.53 (s, 1H), 7.33 (d, J=8.0 Hz,1H), 7.29-7.26 (m, 1H), 6.95 (s, 1H), 6.33 (t, J=5.6 Hz, 1H), 5.05 (s,1H), 4.37-4.35 (d, J=5.6 Hz, 2H), 3.88 (s, 3H).

Example 11-E Synthesis of Compound 536

Preparation of compound 3 was followed the general procedure. A mixtureof compound 3 (2.9 g, 8.5 mmol) and Pd/C (0.29 g) in methanol (20 mL)was stirred under H₂ at rt for 3 hours. The mixture was filtered andconcentrated to give compound 4 (2.7 g, 98% yield).

A mixture of compound 4 (2.5 g, 8 mmol) in aq. HBr (40%, 20 mL) wasstirred at 90° C. for 12 hrs. After being cooled to rt, the mixture waspoured into water, neutralized with NaHCO₃, and then extracted withDCM/i-PrOH. The combined organic layer was washed with brine, dried overanhydrous Na₂SO₄, and concentrated in vacuo to afford crude compound 5(2.05 g, 86% yield).

Compound 5 (2.4 g, 0.008 mol) in POCl₃ (20 mL) was stirred at 100° C.for 2 h. After completion, the residue was diluted with H₂O andextracted with EtOAc. Following general workup procedure, the residuewas purified by flash chromatography (PE:EA=1:1) to give compound 6 (560mg, 22% yield).

A mixture of compound 6 (300 mg, 0.95 mmol), KOH (107 mg, 1.91 mmol) inDMF (20 mL) was added phenol (134 mg, 1.4 mmol). The mixture was stirredat 130° C. for 2 h. After cooled to rt, the mixture was diluted with H₂Oand extracted with EtOAc. After general workup procedure, the residuewas purified by prep-HPLC to give compound 7 (232 mg, 65% yield).

To a solution of compound 7 (240 mg, 0.62 mmol) in DCM (20 mL) was addedAcCl (0.8 mL, 0.93 mmol). The mixture was stirred at rt for 2 h, and themixture was diluted with DCM (100 mL), the organic layer was washed withwater, brine, dried over anhydrous Na₂SO₄ and concentrated, the residuewas purified by prep.TLC (PE/EA=3/1) to give Compound 536 (132 mg, 52%yield). ¹H NMR (DMSO-d₆, 400 MHz) δ 10.12 (s, 1H), 7.72 (m, 2H),7.67-7.63 (m, 2H), 7.54-7.48 (m, 3H), 7.41-7.37 (m, 1H), 7.34-7.33 (m,1H), 7.29-7.26 (m, 2H), 7.23-7.21 (m, 2H), 7.11-7.09 (m, 1H), 5.35 (s,1H), 2.03 (s, 3H). MS (ESI) m/z (M+H)⁺ 415.1.

Compound 537 was prepared following the similar procedure for thesynthesis of Compound 536, using Compound 539 in place of Compound 1.The hydrogenation step was conducted after the substitution of phenol.TMS-NCO was used in place of AcCl. ¹H NMR (DMSO-d₆, 400 MHz) δ 8.86 (s,1H), 8.06 (s, 1H), 7.93 (s, 1H), 7.84 (s, 1H), 7.57-7.53 (m, 3H),7.39-7.30 (m, 5H), 6.93-6.91 (m, 1H), 5.98 (s, 2H), 5.35 (s, 1H), 3.84(s, 3H). MS (ESI) m/z (M+H)⁺ 402.0.

Compound 545 was prepared following the similar procedure for thesynthesis of Compound 536 using (4-methoxyphenyl)boronic acid in placeof Compound 1. The hydrogenation and reaction with AcCl steps wereeliminated.

Compound 540: To a solution of Compound 545 (200 mg, 0.56 mmol) in DMF(5 mL), 1-chloro-2-methoxyethane (68 mg, 0.72 mmol) and K₂CO₃ (155 mg,1.12 mmol) was added. The mixture was stirred at 100° C. overnight, thendiluted with water and extracted with EA. After standard workupprocedure, the residue was purified by prep-TLC (PE:EA=1:1) to giveCompound 540 (100 mg, yield 43%)¹H NMR (CDCl₃, 400 MHz) δ 7.74 (s, 1H),7.68 (s, 1H), 7.51 (s, 1H), 7.45 (t, J=8.0 Hz, 2H), 7.30 (d, J=8.8 Hz,2H), 7.26 (s, 1H), 7.16 (d, J=8.0 Hz, 2H), 7.03 (d, J=8.8 Hz, 2H), 5.79(s, 1H), 4.16 (t, J=4.8 Hz, 2H), 3.93 (s, 3H), 3.77 (t, J=4.8 Hz, 2H),3.46 (s, 3H). MS (ESI) m/z (M+H)⁺ 418.1.

Example 12-A Synthesis of 4-Methyl, 5-Phenyl Pirfenidone Analogs (SchemeXXVII)

XXVII-3: To a solution of XXVII-1 (1 eq.) in DCM (0.1 mmol/mL) was addedthe relevant boronic acid XXVII-2 (1.5-2 eq.), Cu(OAc)₂ (1˜3 eq),Pyridine (10 eq.) and Pyridine-N-Oxide (2-3 eq.), followed by additionof 4 Å molecular sieve (200-500 mg). The reaction mixture was stirred atrt under oxygen atmosphere overnight. After completion of the reactionindicated by TLC, the resulting mixture was filtered and washed withethyl acetate; the filtrate was washed with brine, dried over Na₂SO₄ andconcentrated. The residue was purified by flash chromatography on silicagel to give the final product.

Three general procedures for the preparation of XXVII-5:

Method A:

To a mixture of XXVII-3 (1 eq.), the relevant boronic acid XXVII-4 (1.2eq.) and K₂CO₃ (2 eq.) in DME/H₂O (v/v=6/1) was added Pd(dppf)Cl₂ (0.1eq.). The reaction mixture was degassed by purging with nitrogen andthen was heated to reflux overnight. After the completion of thereaction, the mixture was cooled to rt, concentrated in vacuo. Theresidue was diluted with water and extracted with EtOAc. The combinedorganic layer was washed with brine, dried over Na₂SO₄, and concentratedunder reduced pressure. The residue was purified by flash chromatographyon silica gel to afford the final product.

Method B:

To a mixture of XXVII-3 (1 eq.), the relevant boronic acid XXVII-4 (1.2eq.) and Na₂CO₃ (2 eq.) in toluene/EtOH/H₂O (v/v/v=5/2/1) was addedPd(PPh₃)₄ (0.1 eq.). The reaction mixture was degassed by purging withnitrogen and then was heated to reflux overnight. After the completionof the reaction, the mixture was cooled to rt, concentrated in vacuo.The residue was diluted with water and extracted with EtOAc. Thecombined organic layer was washed with brine, dried over Na₂SO₄, andconcentrated under reduced pressure. The residue was purified by flashchromatography on silica gel to afford the final product.

Method C:

To a mixture of XXVII-3 (1 eq.), boronic acid XXVII-4 (1.2 eq.) andNa₂CO₃ (2 eq.) in toluene/H₂O (v/v=5/1) was added Pd(dppf)Cl₂ (0.1 eq.).The reaction mixture was degassed by purging with nitrogen and then washeated to reflux overnight. After the completion of the reaction, themixture was cooled to rt, concentrated in vacuo. The residue was dilutedwith water and extracted with EtOAc. The combined organic layer waswashed with brine, dried over Na₂SO₄, and concentrated under reducedpressure. The residue was purified by flash chromatography on silica gelto afford the final product.

Compounds 163-171, 191, 194, 201-205, 552 were prepared following theMethod A as described above. Compounds 172-177 were prepared followingthe Method B as described above. Compounds 195-198 were preparedfollowing the Method C as described above.

Compound 163: ¹H NMR (CDCl₃, 400 MHz) δ 7.69-7.60 (m, 4H), 7.44-7.35 (m,3H), 7.30-7.26 (m, 2H), 7.20 (s, 1H), 6.60 (s, 1H), 2.16 (s, 3H).

Compound 164: ¹H NMR (CDCl₃, 400 MHz) δ 7.50-7.47 (m, 2H), 7.43-7.38 (m,3H), 7.35-7.31 (m, 2H), 7.30-7.26 (m, 2H), 7.21 (s, 1H), 6.60 (s, 1H),2.16 (s, 3H).

Compound 165: ¹H NMR (CDCl₃, 400 MHz) δ 7.50-7.35 (m, 8H), 7.30-7.26 (m,2H), 7.22 (s, 1H), 6.59 (s, 1H), 2.16 (s, 3H).

Compound 166: ¹H NMR (CDCl₃, 400 MHz) δ 7.53-7.49 (m, 1H), 7.44-7.37 (m,4H), 7.34 (s, 1H), 7.30-7.19 (m, 3H), 7.19 (s, 1H), 6.59 (s, 1H), 2.16(s, 3H).

Compound 167: ¹H NMR: (CDCl₃, 400 MHz) δ 8.67 (s, 1H), 7.69 (s, 1H),7.44-7.27 (m, 8H), 7.01 (d, J=7.6 Hz, 1H), 6.66 (s, 1H), 2.21 (s, 3H),2.01 (s, 3H).

Compound 168: ¹H NMR: (CDCl₃, 400 MHz) δ 7.43-7.35 (m, 3H), 7.32-7.28(m, 2H), 7.17 (s, 1H), 7.13 (d, J=8.8 Hz, 1H), 6.84-6.78 (m, 3H), 4.04(q, J=7.6 Hz, 2H), 2.22 (s, 3H), 2.15 (s, 3H), 1.42 (t, J=7.6 Hz, 3H).

Compound 169: ¹H NMR: (CDCl₃, 400 MHz) δ 7.98 (s, 1H), 7.44-7.35 (m,3H), 7.29-7.25 (m, 3H), 7.22-7.18 (m, 1H), 7.03 (d, J=8.4 Hz, 1H), 6.79(s, 1H), 2.28 (s, 3H), 2.20 (s, 3H).

Compound 170: ¹H NMR: (CDCl₃, 400 MHz) δ 7.78 (d, J=8.4 Hz, 2H), 7.60(d, J=8.0 Hz, 2H), 7.45-7.38 (m, 3H), 7.30-7.27 (m, 3H), 6.77 (s, 1H),2.21 (s, 3H).

Compound 171: ¹H NMR: (CDCl₃, 400 MHz) δ 7.50-7.41 (m, 5H), 7.31-7.25(m, 5H), 6.87 (s, 1H), 2.24 (s, 3H).

Compound 172: ¹H NMR (CDCl₃, 400 MHz) δ 9.07 (s, 1H), 7.67 (s, 1H),7.29-7.21 (m, 5H), 7.12-7.07 (m, 2H), 6.95-6.93 (m, 1H), 6.60 (s, 1H),2.17 (s, 3H), 1.95 (s, 3H). MS (ESI) m/z [M+H]⁺ 337.0.

Compound 173: ¹H NMR (CDCl₃, 400 MHz) δ 7.75 (d, J=8.4 Hz, 2H), 7.58 (d,J=8.4 Hz, 2H), 7.27-7.24 (m, 2H), 7.18 (s, 1H), 7.13-7.09 (m, 2H), 6.59(s, 1H), 2.13 (s, 3H). MS (ESI) m/z [M+H]⁺ 348.0.

Compound 174: ¹H NMR (CDCl₃, 400 MHz) δ 7.54-7.50 (m, 1H), 7.41-7.38 (m,1H), 7.33 (s, 1H), 7.29-7.24 (m, 3H), 7.17 (s, 1H), 7.10 (t, J=8.4 Hz,2H), 6.58 (s, 1H), 2.13 (s, 3H). MS (ESI) m/z [M+H]⁺ 364.0.

Compound 175: ¹H NMR (CDCl₃, 400 MHz) δ 7.26-7.22 (m, 2H), 7.13-7.06 (m,4H), 6.84-6.78 (m, 2H), 6.58 (s, 1H), 4.04 (q, J=6.8 Hz, 2H), 2.16 (m,3H), 2.14 (m, 3H), 1.42 (t, J=6.8 Hz, 3H). MS (ESI) m/z [M+H]⁺ 338.2.

Compound 176: ¹H NMR (CDCl₃, 400 MHz) δ 7.50-7.46 (m, 2H), 7.43-7.41 (m,3H), 7.26-7.23 (m, 2H), 7.20 (s, 1H), 7.12-7.07 (m, 2H), 6.58 (s, 1H),2.13 (s, 3H). MS (ESI) m/z [M+H]⁺ 280.1.

Compound 177: ¹H NMR (CDCl₃, 400 MHz) δ 7.77-7.68 (m, 4H), 7.35-7.31 (m,2H), 7.26-7.17 (m, 3H), 6.67 (s, 1H), 2.21 (s, 3H). MS (ESI) m/z [M+H]⁺348.1.

Compound 191: ¹H NMR (CD₃OD, 400 MHz) δ 7.61-7.57 (m, 2H), 7.52 (s, 1H),7.46-7.41 (m, 5H), 7.32-7.30 (m, 1H), 6.59 (s, 1H), 2.22 (s, 3H). MS(ESI) m/z (M+H)⁺ 380.0.

Compound 194: ¹H NMR (CDCl₃, 400 MHz) δ 7.51-7.48 (m, 2H), 7.41-7.32 (m,3H), 7.27-7.13 (m, 4H), 6.60 (s, 1H), 2.11 (s, 3H). MS (ESI) m/z (M+H)⁺364.1.

Compound 195: ¹H NMR (CDCl₃, 400 MHz) δ 7.50-7.45 (m, 3H), 7.36-7.32 (m,2H), 7.24-7.19 (m, 2H), 7.15-7.10 (m, 1H), 6.58 (s, 1H), 2.13 (s, 3H).

Compound 196: ¹H NMR (CDCl₃, 400 MHz) δ 7.49-7.45 (m, 2H), 7.36-7.32 (m,2H), 7.24-7.19 (m, 2H), 7.15-7.10 (m, 1H), 7.03-6.99 (m, 1H), 6.58 (s,1H), 2.13 (s, 3H).

Compound 197: ¹H NMR (CDCl₃, 400 MHz) δ 7.50-7.47 (m, 3H), 7.40 (s, 1H),7.37-7.32 (m, 2H), 7.18 (s, 1H), 7.13 (d, J=8.0 Hz, 1H), 6.60 (s, 1H),2.15 (s, 3H).

Compound 198: ¹H NMR (CDCl₃, 400 MHz) δ 7.48-7.42 (m, 3H), 7.36-7.32 (m,2H), 7.20 (s, 1H), 7.10 (m, 1H), 7.02 (m, 1H), 6.59 (s, 1H), 2.15 (s,3H).

Compound 201: ¹H NMR (CDCl₃, 400 MHz) δ 7.48-7.46 (m, 2H), 7.35-7.30 (m,2H), 7.16 (s, 1H), 6.90-6.88 (m, 1H), 6.78 (s, 1H), 6.75-6.71 (m, 1H),6.56 (s, 1H), 4.29 (s, 4H), 2.16 (s, 3H). MS (ESI) m/z (M+H)⁺ 404.0.

Compound 202: ¹H NMR (CDCl₃, 400 MHz) δ 7.50-7.47 (m, 2H), 7.35-7.31 (m,2H), 7.17 (s, 1H), 6.85-6.82 (m, 1H), 6.75-6.70 (m, 2H), 6.56 (s, 1H),6.00 (s, 2H), 2.15 (s, 3H). MS (ESI) m/z (M+H)⁺ 389.9.

Compound 203: Na₂CO₃ was used instead of K₂CO₃. ¹H NMR (CDCl₃, 400 MHz)δ 7.49-7.47 (m, 2H), 7.34-7.30 (m, 2H), 6.90-6.86 (m, 2H), 6.72-6.70 (m,2H), 6.60 (s, 1H), 5.99 (s, 2H), 2.19 (s, 3H). MS (ESI) m/z [M+H]⁺390.1.

Compound 204: Pd(PPh₃)₄ was used instead of Pd(dppf)Cl₂, and Na₂CO₃ wasused instead of K₂CO₃. ¹H NMR (CDCl₃, 400 MHz) δ 7.51-7.49 (m, 2H),7.34-7.30 (m, 2H), 7.18 (s, 1H), 6.93-6.84 (m, 2H), 6.72-6.70 (m, 1H),6.56 (s, 1H), 4.28 (s, 4H), 2.09 (s, 3H). MS (ESI) m/z [M+H]⁺ 403.9.

Compound 205: 5-bromo-4-(trifluoromethyl)pyridin-2(1H)-one was usedinstead of XXVII-1. Na₂CO₃ was used instead of K₂CO₃. ¹H NMR (CDCl₃, 400MHz) δ 7.50-7.48 (m, 2H), 7.37 (d, J=8.4 Hz, 2H), 7.32-7.26 (m, 3H),7.11-7.07 (m, 3H). MS (ESI) m/z [M+H]⁺ 417.8.

Compound 552: ¹H NMR (CDCl₃, 400 MHz) δ 9.04 (s, 1H), 8.05 (s, 1H), 7.98(d, J=8.4 Hz, 1H), 7.39-7.36 (m, 1H), 7.17-7.13 (m, 2H), 6.84 (s, 1H),6.80 (dd, J=1.6, 4.4 Hz, 1H), 8.16 (dd, J=2.4, 8.4 Hz, 1H), 6.62 (s,1H), 4.04 (q, J=7.2 Hz, 2H), 2.20 (s, 3H), 2.19 (s, 3H), 1.41 (t, J=7.2Hz, 3H). MS (ESI) m/z (M+H)⁺ 377.1.

Example 12-B Synthesis of 4-Methyl, 5-Phenyl Pirfenidone Analogs (SchemeXXVIII)

XXVIII-3 was prepared following Method A for obtaining XXVII-5.

XXVIII-4: A mixture of XXVIII-3 in aq. HBr (48%) was stirred at 100° C.overnight. After being cooled to rt, the mixture was concentrated invacuo. The remaining mixture was neutralized with saturated aq.NaHCO₃,and extracted with EtOAc (30 mL×3). The combined organic layer waswashed with water and brine, dried over anhydrous Na₂SO₄, andconcentrated in vacuo to afford the crude XXVIII-4.

Three general procedures for the preparation of XXVIII-5:

Method 1:

To a solution of XXVIII-4 (1 eq.) in DCM (0.1 mmol/mL) was added therelevant boronic acid XXVIII-2 (1.5-2 eq.), Cu(OAc)₂ (1˜3 eq), pyridine(10 eq.) and Pyridine-N-Oxide (2-3 eq.), followed by addition of 4 Åmolecular sieve (200˜500 mg). The reaction mixture was stirred at rtunder oxygen atmosphere overnight. After completion of the reactionindicated by TLC, the resulting mixture was filtered and washed withethyl acetate; the filtrate was washed with brine, dried over Na₂SO₄ andconcentrated. The residue was purified by flash chromatography on silicagel to give the title compound. Compounds 181-183, 178-180, 192 and 193were prepared following Method 1.

Compound 178: ¹H NMR (CDCl₃, 400 MHz) δ 7.43-7.39 (m, 2H), 7.28-7.23 (m,5H), 7.12-7.08 (m, 3H), 6.60 (s, 1H), 2.13 (s, 3H). MS (ESI) m/z [M+H]⁺298.0.

Compound 179: ¹H NMR (CDCl₃, 400 MHz) δ 7.34 (s, 1H), 7.30-7.21 (m, 3H),7.16 (d, J=8.4 Hz 1H), 7.12-7.07 (m, 2H), 7.02 (s, 1H), 6.59 (s, 1H),2.19 (s, 3H), 2.15 (s, 3H). MS (ESI) m/z [M+H]⁺ 327.9.

Compound 180: ¹H NMR (CDCl₃, 400 MHz) δ 7.38-7.33 (m, 2H), 7.18 (s, 1H),7.09 (t, J=8.8 Hz, 2H), 6.60 (s, 2H), 6.57 (s, 1H), 3.85 (s, 9H), 2.13(s, 3H). MS (ESI) m/z (M+H)⁺370.1.

Compound 192: ¹H NMR (CDCl₃, 400 MHz) δ 7.49-7.46 (m, 2H), 7.45-7.32 (m,3H), 7.20 (s, 1H), 7.09-7.00 (m, 2H), 6.98 (m, 1H), 6.58 (s, 1H), 2.16(s, 3H). MS (ESI) m/z (M+H)⁺364.0.

Compound 193: ¹H NMR (CDCl₃, 400 MHz) δ 7.38-7.34 (m, 1H), 7.33-6.98 (m,5H), 6.84-6.78 (m, 2H), 6.58 (s, 1H), 4.04 (q, J=7.2 Hz, 2H), 2.17 (s,6H), 1.42 (t, J=7.2 Hz, 3H). MS (ESI) m/z (M+H)⁺ 338.1.

Compound 181: ¹H NMR (CDCl₃, 400 MHz) δ 7.50 (d, J=8.8 Hz, 2H), 7.38 (d,J=8.8 Hz, 2H), 7.28-7.23 (m, 3H), 7.13 (t, J=8.4 Hz, 2H), 6.86 (s, 1H),2.21 (s, 3H).

Compound 182: ¹H NMR (CDCl₃, 400 MHz) δ 7.25-7.21 (m, 2H), 7.16 (s, 1H),7.08 (t, J=8.4 Hz, 2H), 6.95-9.92 (m, 2H), 6.88-6.85 (m, 1H), 6.56 (s,1H), 4.28 (s, 4H). 2.11 (s, 3H).

Compound 183: ¹H NMR (CDCl₃, 400 MHz) δ 7.26-7.22 (m, 2H), 7.16 (s, 1H),7.09 (t, J=8.4 Hz, 2H), 6.92 (s, 1H), 6.88-6.80 (m, 2H), 6.56 (s, 1H).6.02 (s, 2H), 2.12 (s, 3H).

Method 2:

To a stirred mixture of 5-(4-fluorophenyl)-4-methylpyridin-2(1H)-one(203 mg, 1 mmol, 1.0 eq.), 1-bromo-2-methyl-4-(trifluoromethoxy)benzene(382 mg, 1.5 mmol, 1.5 eq.), and K₂CO₃ (276 mg, 2 mmol, 2.0 eq.) in DMF(5 mL) was added CuI (19 mg, 0.1 mmol, 0.1 eq.). The reaction mixturewas stirred at 140° C. for 3 days under N₂ protection. The mixture wascooled to rt, diluted with EA (50 mL), washed with water and brine,concentrated. The residue was purified by flash chromatography on silicagel (PE: EA=5:1→1:1) to give Compound 186 (40 mg, 11% yield). ¹H NMR(CDCl₃, 400 MHz) δ 7.27-7.17 (m, 8H), 7.12-7.07 (m, 1H), 6.60 (s, 1H),2.23 (s, 3H), 2.15 (s, 3H). MS (ESI) m/z [M+H]⁺ 378.0.

XXVIII-5a was prepared from XXVIII-4a following Method 2 as describedabove. XXVIII-6a was prepared by hydrogenation (50 Psi) of XXVIII-5a inethanol at rt for 4 h. Compound 557 was obtained from reacting XXVIII-6awith TMS-NCO. ¹H NMR (DMSO-d₆, 400 MHz) δ 8.21 (d, J=8 Hz, 1H), 7.99 (s,1H), 7.93 (s, 1H), 7.42-7.39 (m, 2H), 7.30-7.26 (m, 2H), 7.09 (t, J=7.6Hz, 1H), 7.01 (m, 2H), 6.93 (m, 1H), 6.17 (s, 2H), 2.26 (s, 3H). MS(ESI) m/z [M+H]⁺ 338.0.

Method 3:

To a stirred mixture of 5-(4-fluorophenyl)-4-methylpyridin-2(1H)-one(2.04 g, 10 mmol, 1.0 eq.), 4-bromobenzo[d][1,3]dioxole (3.0 g, 15 mmol,1.5 eq.), and K₂CO₃ (2.76 g, 20 mmol, 2 eq.) in DMF (50 mL) was addedCuI (191 mg, 1 mmol, 0.1 eq.) and 8-hydroxyquinoline (140 mg, 1 mmol,0.1 eq.). The reaction mixture was stirred at 140° C. for 3 days underN₂ protection. The mixture was cooled to rt, diluted with EA (250 mL),washed with water and brine, concentrated. The residue was purified byflash chromatography on silica gel (PE:EA=5:1→1:1) to yield Compound 184(680 mg, 21% yield) as white solid. ¹H NMR (CDCl₃, 400 MHz) δ 7.35-7.32(m, 2H), 7.26 (s, 1H), 7.18 (t, J=8.8 Hz, 2H), 7.02-6.94 (m, 3H), 6.67(s, 1H), 6.13 (s, 2H), 2.21 (s, 3H). MS (ESI) m/z [M+H]⁺ 323.8.

Compound 185 was prepared following the similar procedure for obtainingCompound 184 using 5-bromo-2,3-dihydrobenzo[b][1,4]dioxine in place of4-bromobenzo[d][1,3]dioxole. ¹H NMR (CDCl₃, 400 MHz) δ 7.28-7.24 (m,3H), 7.11-7.06 (m, 3H), 6.94-6.88 (m, 3H), 6.57 (s, 1H), 4.30-4.28 (m,4H), 2.13 (s, 3H). MS (ESI) m/z [M+H]⁺ 338.1.

Compound 187: To the solution of Compound 172 (378 mg, 1.12 mmol) inEtOH/H₂O (10 mL, v/v=2/1) was added aq.H₂SO₄ (6 M, 2 mL). The mixturewas heated to reflux overnight. LCMS showed the reaction was completed.The mixture was concentrated, extracted with EtOAc (30 mL×3). Thecombined organic layer was washed with brine, dried over anhydrousNa₂SO₄ and concentrated. The residue was purified by prep-TLC(PE/EA=3/1) to give Compound 187 (200 mg, 60% yield). ¹H NMR (CDCl₃, 400MHz) δ 7.26-7.21 (m, 3H), 7.18 (s, 1H), 7.11-7.06 (m, 2H), 6.75-6.68 (m,3H), 6.56 (s, 1H), 2.12 (s, 3H).

Compound 188: To the solution of Compound 187 (80 mg, 0.102 mmol) inTHF/H₂O (2 mL, v/v=4/1) was added KOCN (10 mg, 0.112 mmol) and AcOH (onedrop). The mixture was heated to reflux overnight. LCMS showed thereaction was completed. The mixture was concentrated, diluted with EtOAc(50 mL), washed with brine, dried over anhydrous Na₂SO₄ andconcentrated. The residue was purified by prep-HPLC to give Compound 188(62.2 mg, 67% yield). ¹H NMR (CDCl₃, 400 MHz) δ 8.12 (s, 1H), 7.62 (s,1H), 7.24-7.21 (m, 3H), 7.13-7.08 (m, 2H), 6.88 (d, J=8.8 Hz, 1H), 6.81(d, J=8.0 Hz, 1H), 6.60 (s, 1H), 4.84 (s, 2H), 2.18 (s, 3H).

Compound 559 was prepared reacting XXVIII-4a with 2-fluoro-5-iodoanilineusing Method 3 as described above, followed by reacting with TMS-NCO. ¹HNMR (DMSO-d₆, 400 MHz) δ 8.53 (s, 1H), 8.19 (d, J=6.0 Hz, 1H), 7.44-7.40(m, 3H), 7.29-7.20 (m, 3H), 6.97 (m, 1H), 6.43 (s, 1H), 6.27 (s, 2H),2.08 (s, 3H).

Example 12-C Synthesis of Compound 199 (Scheme XXIX)

To a stirred mixture of Compound 87 (200 mg, 0.52 mmol), XXIX-1 (92 mg,0.68 mmol), and Na₂CO₃ (60 mg, 1.4 mmol) in DME/H₂O (18 mL, V/V=8/1) wasadded Pd(dppf)Cl₂ (140 mg, 0.99 mmol) under N₂ protection. The reactionmixture was stirred at 110° C. overnight. The mixture was concentratedto remove DME, diluted with H₂O, extracted with EtOAc (30 mL×3), theorganic layer was washed with water and brine, dried over anhydrousNa₂SO₄, and concentrated in vacuo, the residue was purified by prep-TLC(PE:EA=2.5:1) to give XXIX-2 (112 mg, yield: 57%) as a white solid. MS(ESI) m/z [M+H]⁺ 376.09.

XXIX-2 (170 mg, 0.45 mmol), TsNHNH₂ (338 mg, 1.81 mmol), and NaOAc (371mg, 4.53 mmol) were added into DME/H₂O (20 mL, v/v=5/1). The reactionmixture was stirred at 110° C. overnight. The mixture was concentratedto remove DME, diluted with H₂O, extracted with EtOAc (30 mL×3), theorganic layer was washed with water and brine, dried over anhydrousNa₂SO₄, and concentrated in vacuo, the residue was purified by prep-HPLCto afford Compound 199 (107 mg, yield 64%) as white solid. ¹H NMR(CDCl₃, 400 MHz) δ 7.49-7.46 (m, 2H), 7.33-7.31 (m, 2H), 7.26-7.22 (m,2H), 7.14 (s, 1H), 7.11-7.06 (m, 2H), 6.60 (s, 1H), 2.46-2.41 (m, 2H),1.12-1.07 (m, 3H). MS (ESI) m/z [M+H]⁺ 378.10.

Example 12-D Synthesis of Compound 200 (Scheme XXX)

To a stirred mixture of Compound 87 (150 mg, 0.270 mmol), XXX-1 (135 mg,0.4 mmol), and K₂CO₃ (186 mg, 1.35 mmol) in toluene (5 mL) was addedPd(PPh₃)₄ (30 mg, 0.0270 mmol). The mixture was purged with nitrogen forthree times and then heated at 120° C. overnight. And then the mixturewas concentrated, diluted with H₂O, extracted with EtOAc (30 mL×3), theorganic layer was washed with water and brine, dried over anhydrousNa₂SO₄, and concentrated in vacuo. The crude product was purified byprep-TLC (PE:EA=5:1) to yield XXX-2 (135 mg, 88% yield).

A mixture of XXX-2 (100 mg, 0.259 mmol) and dry Pd/C in ethanol (5 mL)was stirred under H₂ at rt for 1 h. Filtered the reaction, andconcentrated the organic layer to give Compound 200 (61.6 mg, 61%yield). ¹H NMR (CDCl₃, 400 MHz) δ 7.49 (d, J=8.8 Hz, 2H), 7.34 (d, J=8.4Hz, 2H), 7.25-7.23 (m, 2H), 7.14-7.08 (m, 3H), 6.65 (s, 1H), 2.85-2.77(m, 1H), 1.14 (d, J=6.8 Hz, 6H).

Compound 629: To a mixture of5-bromo-1-(4-ethoxy-2-methylphenyl)-4-methylpyridin-2(1H)-one (1.5 g,4.66 mmol) and 4-(tributylstannyl)pyridazine (3.44 g, 9.31 mmol) indioxane (20 mL) was added Pd(PPh₃)₂Cl₂ (0.163 g, 0.233 mmol) under N₂ atrt. The mixture was refluxed overnight. The mixture was concentrated,diluted with water and extracted with EtOAc. The organic layer werewashed with brine, dried over Na₂SO₄, and concentrated under reducedpressure. The residue was purified by chromatography on silica gel(PE/EA=1:2→EA) to produce Compound 629 as a yellow solid (0.806 g, 54%yield). ¹H NMR (DMSO-d₆, 400 MHz) δ 9.33 (d, J=2.4 Hz, 1H), 9.21 (d,J=5.6 Hz, 1H), 7.78 (dd, J=2.4, 5.2 Hz, 1H), 7.70 (s, 1H), 7.18 (d,J=8.8 Hz, 1H), 6.92 (d, J=2.4 Hz, 1H), 6.85 (dd, J=2.4, 8.4 Hz, 1H),6.50 (s, 1H), 4.07 (q, J=6.8 Hz, 2H), 2.21 (s, 3H), 2.04 (s, 3H), 1.32(t, J=6.8 Hz, 3H). MS (ESI) m/z [M+H]⁺ 322.0.

Example 12-D Synthesis of Compound 189 (Scheme XXXI)

XXXI-3 was obtained following the similar procedure for obtainingXXVII-3.

To a solution of XXXI-3 (300 mg, 0.854 mmol) in EtOH (10 mL) was added asolution of NaOH (102 mg, 2.56 mmol) in water (8 mL). The reactionmixture was heated to 100° C. for 4 hrs. After concentration in vacuo,the mixture was acidified with aq. HCl (1N). Then the mixture wasextracted with EtOAc (30 mL×3). The combined organic layer was washedwith brine, dried over anhydrous Na₂SO₄ and concentrated. The crudeproduct was used for next step directly without further purification(200 mg, 72% yield). MS (ESI) m/z [M+H]⁺ 324.0.

XXXI-4 (150 mg, 0.464 mmol), HOBT (70 mg, 0.51 mmol), EDC.HCl (100 mg,0.51 mmol) and DIEA (260 mg, 2 mmol) were charged into dry DCM (5 mL),followed by NH₄Cl (75 mg, 1.4 mmol). The reaction mixture was stirred atrt overnight. The mixture was diluted with water (10 mL), extracted withEtOAc (20 mL×3). The combined organic layer was washed with brine, driedover anhydrous Na₂SO₄ and concentrated. The residue was purified byprep-HPLC to afford Compound 189 as a pale yellow solid (21.8 mg, 17%yield). ¹H NMR (CDCl₃, 400 MHz) δ 7.89 (s, 1H), 7.84 (m, 1H), 7.59-7.53(m, 2H), 7.27-7.22 (m, 3H), 7.13-6.99 (m, 2H), 6.56 (s, 1H), 2.14 (s,3H). MS (ESI) m/z (M+Na)⁺ 344.9.

Compound 190: To a solution of XXXI-4 (250 mg, 0.77 mmol), HATU (350 mg,0.92 mmol), and DIEA (300 mg, 2.3 mmol) in dry DCM (8 mL) was added themethylamine hydrochloride (78 mg, 1.16 mmol). The reaction mixture wasstirred at rt overnight. The mixture was diluted with water (20 mL),extracted with EtOAc (30 mL×3). The combined organic layer was washedwith brine, dried over anhydrous Na₂SO₄ and concentrated. The residuewas purified by prep-TLC (DCM:MeOH=10:1) to produce Compound 190 as awhite solid (159.3 mg, 61% yield). ¹H NMR (CDCl₃, 400 MHz) δ 7.81 (s,1H), 7.75 (m, 1H), 7.52-7.46 (m, 2H), 7.27-7.21 (m, 3H), 7.13-7.08 (m,2H), 6.70 (brs, 1H), 6.57 (s, 1H), 2.96 (d, J=4.8 Hz, 3H), 2.14 (s, 3H).MS (ESI) m/z (M+H)+336.9.

Example 12-E Synthesis of Compound 206 (Scheme XXXII)

To a stirred mixture of XXXII-1 (1.5 g, 9.15 mmol), XXXII-2 (1.83 g,9.15 mmol), and K₂CO₃ (3.79 g, 27.45 mmol) in DME/H₂O (50 mL, v:v=5:1)was added Pd(dppf)Cl₂ (1.34 g, 1.83 mmol) under N₂ protection. Thereaction mixture was heated to reflux overnight. The mixture was pouredinto water, extracted with EtOAc (150 mL×3). The combined organic layerwas washed with brine, dried over anhydrous Na₂SO₄ and concentrated. Theresidue was purified by flash chromatography on silica gel(PE:EA=10:1→5:1→3:1) to afford XXXII-3 (600 mg, 21% yield).

To a stirred mixture of XXXII-3 (400 mg, 1.7 mmol), XXXII-4 (425.8 mg,2.55 mmol), and K₂CO₃ (703.8 mg, 5.1 mmol) in DME/H₂O (50 mL, v:v=5:1)was added Pd(dppf)Cl₂ (120 mg, 0.17 mmol) under N₂ protection. Thereaction mixture was heated to reflux for 4 hours, then the mixture waspoured into water, extracted with EtOAc (30 mL×3), the organic layer waswashed with brine, dried over anhydrous Na₂SO₄, and concentrated invacuo. The residue was purified by column chromatography on silica gel(PE:EA=3:11:1) to afford XXXII-5 (220 mg, 46% yield). MS (ESI) m/z[M+H]⁺ 283.

A mixture of XXXII-5 (100 mg, 0.35 mmol) in AcOH (5 mL) and aq. HBr(40%, 5 mL) was heated to reflux overnight. And then it was neutralizedwith aq. NaOH (1 M), extracted with EA (30 mL×3). The combined organiclayer was washed with brine, dried over Na₂SO₄, and concentrated invacuo to give XXXII-6 (80 mg, 85% yield). ¹H NMR (DMSO-d₆, 300 MHz) δ9.12 (s, 1H), 8.36 (s, 1H), 7.73-7.70 (d, J=7.8 Hz, 2H), 7.41-7.39 (d,J=8.1 Hz, 2H), 7.25 (s, 1H), 6.30 (s, 1H), 1.90 (s, 3H).

Compound 206 was prepared by following the similar procedure forobtaining XXVII-3 (150 mg, 58% yield). ¹H NMR (CDCl₃, 400 MHz) δ 8.79(s, 1H), 8.12 (s, 1H), 7.63 (d, J=8.4 Hz, 2H), 7.49 (d, J=8.8 Hz, 2H),7.34 (m, 4H), 7.23 (s, 1H), 6.61 (s, 1H), 2.19 (s, 3H). MS (ESI) m/z[M+H]⁺ 429.1.

Example 12-F Synthesis of Compound 207 (Scheme XXXIII)

XXXIII-3 was prepared following the similar procedure for obtainingXXXII-5.

XXXIII-4 was prepared following the similar procedure for obtainingXXXII-6.

To a solution of XXXIII-3 (450 mg, 1.2 mmol) in toluene (50 mL) wasadded 2,2-dimethoxypropane (9 mL) and TsOH (45.6 mg, 0.24 mmol), themixture was heated to reflux overnight. The mixture was poured intowater, extracted with EA (50 mL×3). The combined organic layer waswashed with brine and concentrated to give crude product, which waspurified by prep-HPLC to give Compound 207 (200 mg, 41% yield). ¹H NMR(CDCl₃, 400 MHz) δ 7.49-7.47 (m, 2H), 7.33-7.31 (d, J=8.4 Hz, 2H), 7.24(s, 1H), 6.83-6.79 (m, 1H), 6.77-6.75 (m, 1H), 6.64-6.62 (m, 1H), 6.57(s, 1H), 2.18 (s, 3H), 1.70 (s, 6H). MS (ESI) m/z [M+H]+ 418.

Compound 211 was prepared following the similar procedure for obtainingCompound 207 using (3,4-dimethoxyphenyl)boronic acid in place ofXXXIII-2. ¹H NMR (CDCl₃, 400 MHz) δ 7.49-7.46 (m, 2H), 7.34-7.31 (m,2H), 7.16 (s, 1H), 6.75-6.73 (d, J=7.6 Hz, 1H), 6.67-6.64 (m, 2H), 6.56(s, 1H), 2.16 (s, 3H), 1.70 (s, 6H). MS (ESI) m/z [M+H]+ 417.9.

XXXIII-2a was prepared by following the similar procedure for obtainingXXXIII-3 using bis(pinacolato)diboron in place of XXXIII-2 as a whitesolid.

Compound 415: To a solution of XXXIII-2a (200 mg, 1.06 mmol) in DMF (4mL) was added K₃PO₄ (476 mg 2.11 mmol), XXXIII-3a (500 mg, 3.16 mmol),Pd(PPh₃)₄ (122 mg, 0.106 mmol). The mixture was purged with nitrogen andthen heated at 100° C. overnight. The mixture was cooled to rt, dilutedwith water (20 mL), extracted with EtOAc (30 mL×3). The combined organiclayer was washed with brine, dried over anhydrous Na₂SO₄, andconcentrated in vacuo. The residue was purified by prep-TLC (PE/EA=10/1)to give Compound 415 (128 mg, 36% yield). ¹H NMR (CDCl₃, 400 MHz) δ 7.50(d, J=8.8 Hz, 2H), 7.35 (d, J=8.4 Hz, 2H), 7.29 (s, 1H), 7.15-7.08 (m,2H), 6.98-6.96 (m, 1H), 6.62 (s, 1H), 2.17 (s, 1H). MS (ESI) m/z (M+H)⁺425.9.

Example 12-G Synthesis of Compound 208 (Scheme XXXIV)

A flask was charged with XXXIV-2 (1 g, 4.2 mmol), bis(pinacolato)diboron (1.27 g, 5 mmol) and KOAc (0.5 g, 5 mmol) in1,4-dioxane (30 mL). The flask was purged with nitrogen for three times.And then Pd(dppf)Cl₂ (150 mg, 0.21 mmol) was added thereto and then themixture was purged with nitrogen again. The mixture was stirred at 90°C. for 12 hrs. After the starting material was consumed, the mixture wascooled to rt, the solvent was evaporated in vacuo. The residue wasdiluted with water (30 mL), extracted with EA (50 mL×3). The combinedorganic layer was washed with brine, dried over Na₂SO₄ and concentrated.The residue was purified by column chromatography on silica gel(PE:EA=10:1 to 5:1) to provide XXXIV-2 (800 mg, 67% yield) as a whitesolid.

Compound 208 was obtaining following the similar procedure for obtainingXXXII-5. ¹H NMR (CDCl₃, 400 MHz) δ 7.48-7.45 (m, 2H), 7.33 (d, J=8.4 Hz,2H), 7.18 (s, 1H), 7.11-7.09 (m, 1H), 7.02-6.97 (m, 2H), 6.59 (s, 1H),2.14 (s, 3H). MS (ESI) m/z [M+H]⁺ 425.9.

To a mixture of XXXIV-1 (700 mg, 3.763 mmol) in MeCN (20 mL) was addedBnBr (954 mg, 15.465 mmol) and K₂CO₃ (1.349 g, 7.523 mmol). The mixturewas stirred at rt overnight, and then it was concentrated to removeMeCN, diluted with H₂O, extracted with EtOAc. The organic layer waswashed with water and brine, dried over anhydrous Na₂SO₄, andconcentrated in vacuo. The crude product was chromatographed on silicagel (PE:EA=1:1) to give XXXIV-2 (600 mg, yield 58%). MS (ESI) m/z [M+H]⁺278.2.

XXXIV-3a was prepared from Suzuki-Coupling of XXXIV-2a and bis(pinacolato)diboron following the standard procedure described above.XXXIV-5a was prepared by Suzuki-Coupling of XXXIV-3a with XXXIV-4afollowing the standard procedure described above.

A mixture of XXXIV-5a (250 mg, 0.704 mmol) and Pd(OH)₂/C (25 mg) in EtOH(10 mL) was stirred under 1 atm of H₂ at 50° C. overnight. Aftercompletion of the reaction, the mixture was filtered and concentrated,the residue was purified by prep-TLC (PE/EA=5/1) to afford Compound 565(40 mg, 22% yield). ¹H NMR (CDCl₃, 400 MHz) δ 7.35 (s, 1H), 7.16-7.06(m, 2H), 6.92 (d, J=7.6 Hz, 1H), 6.52 (s, 1H), 2.16 (s, 3H). MS (ESI)m/z (M+H)⁺ 266.1.

Example 12-H Synthesis of Compound 209 (Scheme XXXV)

TEA (4.06 g, 0.04 mmol) was added to a solution of XXXV-1 (5 g, 27 mmol)in THF (150 mL). And then 2-chloroacetyl chloride (3.33 g, 0.03 mmol)was added in portions at 0° C. After 20 minutes, the mixture was stirredat rt for 2 hrs. The reaction mixture was cooled to 0° C. and NaH (60%,2.2 g, 54 mmol) was added in portions. The reaction mixture was stirredat 0° C. for 20 minutes then at rt for 2 h before being quenched withwater. The solvent was removed in vacuo and the resulting mixturediluted with water. The precipitate was filtered, washed with water anddried in vacuo to give XXXV-2 (5.5 g, 89% yield).

To the solution of XXXV-2 (2.3 g, 10 mmol) in dioxane (20 mL), bis(pinacolato)diboron (3.05 g, 12 mmol), potassium acetate (2 g, 20 mmol)and Pd(dppf)Cl₂ (730 mg, 1 mmol) was added. The mixture was purged withnitrogen and stirred at 90° C. overnight. Then the mixture was dilutedwith EA (200 mL) and filtrated. The organic phase was washed with brine,dried over Na₂SO₄, concentrated in vacuo to give the crude product. Theresidue was purification by column chromatography on silica gel(PE:EA=3:1 to 1:1) to give XXXV-4 (1.9 g, 69% yield).

To the solution of XXXV-4 (1.4 g, 5.1 mmol) in dioxane/H₂O (15 mL/3 mL),XXXV-5 (1.47 g, 4.2 mmol), Na₂CO₃ (890 mg, 8.4 mmol) and Pd-118 (137 mg,6.21 mmol) were added. The mixture was purged with nitrogen and stirredat 90° C. overnight. Then the mixture was diluted with EA (100 mL) andfiltrated. The organic phase was washed with brine, dried over Na₂SO₄,concentrated in vacuo to give the crude product. The residue waspurified by column chromatography on silica gel (PE:EA=2:1 to 1:1) toafford Compound 209 (1.36 g, 64% yield). ¹H NMR (CDCl₃, 400 MHz) δ 9.05(s, 1H), 7.49-7.45 (m, 2H), 7.35-7.32 (m, 2H), 7.16 (s, 1H), 7.03-7.00(m, 1H), 6.89-6.87 (m, 1H), 6.74 (s, 1H), 6.58 (s, 1H), 4.65 (s, 2H),2.13 (s, 3H). MS (ESI) m/z (M+H)⁺ 416.9.

Compound 210: Compound 209 (400 mg, 0.96 mmol) was dissolved in THF (2mL), NaH (60%, 60 mg, 1.2 mmol) was added in portions under stirring at0° C. After about 30 minutes, iodomethane (2.1 g, 14.6 mmol) was added;the mixture was stirred at rt for 14 hrs. Then diluted with water andextracted with EA (30 mL×3). The combined organic phase was washed withbrine, dried over Na₂SO₄, concentrated in vacuo to give the crudeproduct, which was purified by prep-TLC (PE:EA=2:1) to provide Compound210 (262 mg, 63% yield). ¹H NMR (CDCl₃, 400 MHz) δ 7.50-7.48 (m, 2H),7.36-7.31 (m, 2H), 7.19 (s, 1H), 7.03-7.00 (m, 1H), 6.91 (d, J=8.0 Hz,1H), 6.87 (s, 1H), 6.59 (s, 1H), 4.66 (s, 2H), 3.38 (s, 3H), 2.15 (s,3H). MS (ESI) m/z (M+H)⁺ 431.0.

XXXV-4a was prepared by following the similar procedure for obtainingXXXV-4 using 2-amino-6-bromophenol in place of XXXV-1.

To the solution of XXV-4a (450 mg, 1.64 mmol) in dioxane/H₂O (10 mL/2mL), XXV-5 (516 mg, 1.49 mmol), Na₂CO₃ (316 mg, 2.98 mmol) and Pd-118(50 mg, 0.08 mmol) was added. The mixture was purged with nitrogen andstirred at 90° C. overnight. Then the mixture was diluted with EA (100mL) and filtered. The organic phase was washed with brine, dried overNa₂SO₄, concentrated in vacuo to give the crude product. The residue waspurified by column chromatography (PE/EA=2/1) to produce Compound 423(440 mg, 65% yield). ¹H NMR (CDCl₃, 400 MHz) δ 8.59 (s, 1H), 7.49 (d,J=8.8 Hz, 2H), 7.32 (d, J=8.4 Hz, 2H), 7.18 (s, 1H), 7.02-6.98 (m, 1H),6.88-6.85 (m, 2H), 6.58 (s, 1H), 4.62 (s, 2H), 2.09 (s, 3H). MS (ESI)m/z (M+H)⁺ 416.9.

To the stirring mixture of Compound 423 (370 mg, 0.89 mmol) in acetone(5 mL), K₂CO₃ (180 mg, 1.33 mmol) and iodomethane (139 mg, 0.98 mmol)were added in portions. The mixture was refluxed overnight. The mixturewas cooled to rt and filtered. The filtrate was concentrated in vacuo togive the crude product. The residue was purified by columnchromatography (PE/EA=2/1) to give Compound 428 (230 mg, 60% yield). ¹HNMR (CDCl₃, 400 MHz) δ 7.49 (d, J=8.8 Hz, 2H), 7.32 (d, J=8.4 Hz, 2H),7.17 (s, 1H), 7.11-7.07 (m, 1H), 7.04-7.02 (m, 1H), 6.91-6.89 (m, 1H),6.58 (s, 1H), 4.62 (s, 2H), 3.40 (s, 3H), 2.08 (s, 3H). MS (ESI) m/z(M+H)⁺ 431.0.

Compounds 424 and 425 were prepared following the similar procedure forobtaining Compounds 423 and 428 using 2-amino-5-bromophenol as startingmaterial.

Compound 424: ¹H NMR (CDCl₃, 400 MHz) δ 8.49 (s, 1H), 7.50-7.46 (m, 2H),7.35-7.31 (m, 2H), 7.18 (s, 1H), 6.91 (s, 1H), 6.89-6.83 (m, 2H), 6.59(s, 1H), 4.65 (s, 2H), 2.16 (s, 3H). MS (ESI) m/z (M+H)⁺ 416.9.

Compound 425: ¹H NMR (CDCl₃, 400 MHz) δ 7.48 (d, J=8.8 Hz, 2H), 7.33 (d,J=8.4 Hz, 2H), 7.19 (s, 1H), 7.01-6.92 (m, 3H), 6.58 (s, 1H), 4.65 (s,2H), 3.39 (s, 3H), 2.17 (s, 3H). MS (ESI) m/z (M+H)⁺ 431.0.

Compounds 426 and 427 were prepared following the similar procedure forobtaining Compounds 423 and 428 using 2-amino-3-bromophenol as startingmaterial.

Compound 426: ¹H NMR (CDCl₃, 400 MHz) δ 8.28 (s, 1H), 7.50 (d, J=8.8 Hz,2H), 7.33 (d, J=8.4 Hz, 2H), 7.23 (s, 1H), 7.02 (d, J=4.8 Hz, 2H),6.85-6.83 (m, 1H), 6.59 (s, 1H), 4.58 (s, 2H), 1.97 (s, 3H). MS (ESI)m/z (M+H)⁺ 416.9.

Compound 427: ¹H NMR (CDCl₃, 400 MHz) δ 7.46 (d, J=9.2 Hz, 2H), 7.34 (d,J=8.4 Hz, 2H), 7.24 (s, 1H), 7.10-7.08 (m, 2H), 6.91-6.89 (m, 1H), 6.63(s, 1H), 4.61-4.50 (m, 2H), 3.04 (s, 3H), 2.07 (s, 3H). MS (ESI) m/z(M+H)⁺ 431.0.

Compound 566 was obtained by reacting Compound 424 with2-(2-bromoethoxy)tetrahydro-2H-pyran in DMF with the presence of Cs₂CO₃,followed by hydroxy group deprotection using TsOH. H₂O. ¹H NMR (CDCl₃,300 MHz) δ 7.47 (d, J=9.0 Hz, 2H), 7.33 (d, J=8.4 Hz, 2H), 7.18-7.13 (m,2H), 6.94 (d, J=7.2 Hz, 2H), 6.58 (s, 1H), 4.67 (s, 2H), 4.16 (t, J=5.4Hz, 2H), 3.98 (m, 2H), 2.16 (s, 3H). MS (ESI) m/z (M+H)⁺ 461.0.

To a solution of XXXV-1 (3 g, 16 mmol) in dry DCM (50 mL) was added TEA(3.2 g, 32 mmol). The reaction mixture was cooled to 0° C., triphosgene(1.6 g, 5.3 mmol) was added slowly. The mixture was stirred overnight atrt, then quenched with water, extracted with DCM (80 mL×3). The combinedorganic layer was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated. The residue was purified by column chromatography onsilica gel (PE/EA=10/1) to afford XXXV-2b (2.7 g, 79% yield).

To a solution of XXXV-2b (500 mg, 2.97 mmol) in dry DCM (20 mL) wasadded TEA (360 mg, 3.56 mmol) and Trt-Cl (992 mg, 3.56 mmol). Themixture was stirred overnight at rt, then poured into water, extractedwith DCM (50 mL×3). The combined organic layer was washed with brine,dried over anhydrous Na₂SO₄, and concentrated in vacuo. The residue waspurified by column chromatography on silica gel (PE/EA=10/1) to affordXXXV-3b (1.2 g, 89% yield).

XXXV-4b was prepared following the similar procedure for obtainingXXXV-4. MS (ESI) m/z (M+H)⁺ 503.9.

XXXV-6b was prepared following the similar procedure described in MethodA. MS (ESI) m/z (M+H)⁺ 645.1.

Compound 429: XXXV-6b (800 mg, 1.24 mmol) was dissolved in a solution ofHCl/MeOH (4 M, 50 mL), the mixture was stirred overnight at 70° C. Andthen the mixture was concentrated, the residue was diluted with water(20 mL) and adjusted to pH=7-8 with saturated aq. NaHCO₃, extracted withEtOAc (80 mL×3). The combined organic layer was washed with brine, driedover anhydrous Na₂SO₄, and concentrated in vacuo. The residue waspurified by column chromatography on silica gel (PE/EA=10/1→5/1) toafford Compound 429 (370 mg, 74% yield).

Compound 430 was prepared following the similar procedure for obtainingCompound 428 using ethyl iodide instead of methyl iodide. ¹H NMR (CDCl₃,400 MHz) δ 7.48-7.46 (m, 2H), 7.34-7.32 (m, 2H), 7.18 (s, 1H), 7.14 (s,1H), 7.11-7.08 (m, 1H), 7.02-7.00 (m, 1H), 6.59 (s, 1H), 3.92 (q, J=7.2Hz, 2H), 2.14 (s, 3H), 1.40 (t, J=7.2 Hz, 3H). MS (ESI) m/z (M+H)⁺431.1.

Compound 553 was prepared following the similar procedure described inthe synthesis of Compound 429 using 2-amino-4-bromophenol in place ofXXXV-1. ¹H NMR (DMSO-d₆, 400 MHz) δ 7.64 (d, J=6.8 Hz, 2H), 7.53-7.49(m, 3H), 7.32 (d, J=8.0 Hz, 1H), 7.10 (d, J=8.4 Hz, 2H), 6.48 (s, 1H),2.13 (s, 3H). MS (ESI) m/z [M+H]+ 403.0.

Compound 554 was prepared following the similar procedure described inthe synthesis of Compound 430. ¹H NMR (DMSO-d₆, 400 MHz) δ 7.66-7.63 (m,2H), 7.58 (s, 1H), 7.53-7.51 (m, 2H), 7.40-7.37 (m, 2H), 7.18-7.15 (m,1H), 6.50 (s, 1H), 3.86 (q, J=6.8 Hz, 2H), 2.16 (s, 3H), 1.26 (t, J=6.8Hz, 3H). MS (ESI) m/z [M+H]+ 431.1.

To a solution of XXXV-1c (200 mg, 1.08 mmol) in dry THF (15 ml) wasadded CDI (262 mg, 1.62 mmol). The reaction mixture was heated to refluxovernight, then quenched with water, extracted with EA, the organiclayer was washed with brine, dried over anhydrous Na₂SO₄, andconcentrated in vacuo. The residue was purified by chromatography onsilica gel (PE:EA=10:1) to afford XXXV-2c (160 mg, yield 70%).

To a solution of XXXV-2c (5.3 g, 25 mmol) in DMF (20 mL) was added NaH(60% dispersion in mineral oil, 1.5 g, 37.5 mmol) at 0° C., The mixturewas stirred for 30 mins at rt, then SEM-Cl (6.2 g, 37.5 mmol) was addedslowly, and then the reaction mixture was stirred overnight at rt. Themixture was poured into water, extracted with EA, the organic layer waswashed with brine, dried over anhydrous Na₂SO₄, and concentrated. Theresidue was purified by chromatography on silica gel (PE:EA=15:15:1) toafford XXXV-3c (2.7 g, yield 31%).

XXXV-4c was prepared following the similar procedure described in thesynthesis of Compound 423. Compound 555 was prepared by acid hydrolysisof XXXV-4c. ¹H NMR (CD₃OD, 400 MHz) δ 7.62-7.57 (m, 3H), 7.45 (d, J=8.4Hz, 2H), 7.22 (d, J=8.0 Hz, 1H), 7.13-7.06 (m, 2H), 6.62 (s, 1H), 2.19(s, 3H). MS (ESI) m/z [M+H]⁺ 403.1.

Compound 556 was prepared following the similar procedure described inthe synthesis of Compound 430. ¹H NMR (CD₃OD, 400 MHz) δ 7.63-7.57 (m,3H), 7.46-7.44 (d, J=8.4 Hz, 2H), 7.31-7.26 (m, 2H), 7.13-7.11 (d, J=7.6Hz, 1H), 6.62 (s, 1H), 3.94 (q, J=7.2 Hz, 2H), 2.18 (s, 3H), 1.36 (t,d=7.2 Hz, 3H). MS (ESI) m/z [M+H]+ 431.0.

Compound 558 was prepared by reacting Compound 429 with(2-bromoethoxy)(tert-butyl)dimethylsilane in acetone with the presenceof K₂CO₃, followed by deprotection of the TBDMS protecting group usingTBAF. ¹H NMR (CDCl₃, 400 MHz) δ 8.19 (s, 1H), 7.47 (d, J=8.8 Hz, 2H),7.33 (d, J=8.4 Hz, 2H), 7.19 (s, 1H), 7.05 (d, J=8.4 Hz, 1H), 7.00 (s,1H), 6.88 (d, J=2.0 Hz, 1H), 6.57 (s, 1H), 4.67 (t, J=8.0 Hz, 2H), 4.19(t, J=8.0 Hz, 2H), 2.17 (s, 3H). MS (ESI) m/z [M+H]⁺ 447.2

XXXV-2d was prepared following the similar procedure described in thesynthesis of XXXV-2c. XXXV-4d was prepared by reacting XXXV-2d withethyl iodide followed by Suzuki-coupling using the standard proceduredescribed in the synthesis of XXXV-4b.

XXXV-6d was prepared by reacting XXXV-4d with XXXV-5d using Method A asdescribed herein. Compound 562 was obtained from acid hydrolysis ofXXXV-6d. 1H NMR (DMSO-d₆, 300 MHz) δ 11.65 (s, 1H), 7.35-7.39 (m, 2H),7.29 (s, 1H), 7.12 (d, J=7.8 Hz, 1H), 6.35 (s, 1H), 3.95 (t, J=6.6 Hz,2H), 2.14 (s, 3H), 1.32 (t, J=6.6 Hz, 3H). MS (ESI) m/z (M+H)⁺ 270.9.

Compound 662 was prepared following the similar procedure described inthe synthesis of Compound 562 using ClCH₂COCl in place of CDI in thereaction with XXXV-1. The subsequent reaction with EtI was eliminated.After the second Suzuki-Coupling reaction, methyl iodide was used tomethylate the proton on the benzo[b][1,4]oxazin-3(4H)-one moiety beforeperforming the HBr hydrolysis. ¹H NMR (DMSO-d₆, 400 MHz) δ 7.21 (s, 1H),7.08 (s, 1H), 7.02 (d, J=8.0 Hz, 1H), 6.96 (d, J=8.0 Hz, 1H), 6.27 (s,1H), 4.67 (s, 2H), 3.29 (s, 3H), 2.07 (s, 3H). MS (ESI) m/z (M+H)⁺270.9.

Compound 663 was prepared following the similar procedure described inthe synthesis of Compound 562 using Trt-Cl in place of EtI in thereaction with XXXV-2d and5-bromo-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)pyridin-2(1H)-onewas used in place of XXXV-5d. Finally, the trityl group was removed byHCl in MeOH solution. ¹H NMR (DMSO-d₆, 400 MHz) δ 11.73 (s, 1H), 7.31(d, J=8.4 Hz, 1H), 7.25 (s, 1H), 7.01 (s, 1H), 7.00 (d, J=6.8 Hz, 1H),6.33 (s, 1H), 2.05 (s, 3H). MS (ESI) m/z (M+H)⁺ 243.1.

XXXV-4e was prepared by following the similar procedure for obtainingXXXV-4 using 2-amino-5-bromophenol in place of XXXV-1. XXXV-6e wasobtained by reacting XXXV-4e with XXXV-5e following the similarprocedure described in the synthesis of Compound 423. Compound 563 wasobtained by methylation of XXXV-6e followed by HBr hydrolysis. ¹H NMR(DMSO-d₆, 400 MHz) δ 11.54 (s, 1H), 7.17-7.15 (m, 2H), 6.99-6.95 (m,2H), 6.24 (s, 1H), 4.65 (s, 2H), 3.27 (s, 3H), 2.04 (s, 3H).

Compound 564 was prepared from XXXV-3b following the synthetic schemedescribed above. ¹H NMR (400 MHz, CDCl₃) δ 7.26-7.23 (m, 1H), 7.10 (s,1H), 7.06-7.00 (m, 2H), 6.49 (s, 1H), 3.92 (q, J=7.2 Hz, 2H), 2.13 (s,3H), 1.42 (t, J=7.2 Hz, 3H). MS (ESI) m/z [M+H]+ 270.9

Compound 567 was prepared by Suzuki-Coupling of XXXV-4 withSEM-protected 5-bromo-4-methylpyridin-2(1H)-one, followed by HClhydrolysis. ¹H NMR (DMSO-d₆, 300 MHz) δ 11.54 (s, 1H), 10.74 (s, 1H),7.14 (s, 1H), 6.97 (d, J=8.0 Hz, 1H), 6.85 (d, J=6.0 Hz, 1H), 6.78 (s,1H), 6.27 (s, 1H), 4.64 (s, 2H), 2.04 (s, 3H). MS (ESI) m/z (M+H)⁺257.0.

Example 13-A Synthesis of 4-Methyl, 5-Pyrazole analogs (Scheme XXXVI)

To a solution of XXXVI-1 (1 eq.) in DME/H₂O (v/v=10/1) was added K₂CO₃(2 eq.), XXXVI-2 (1.5 eq.), Pd(dppf)Cl₂ (0.1 eq.). The mixture waspurged with nitrogen and then heated at reflux overnight. The mixturewas cooled to rt, diluted with water, extracted with EtOAc. The combinedorganic layer was washed with brine, dried over anhydrous Na₂SO₄, andconcentrated in vacuo. The residue was purified by flash chromatographyto give the final product.

Compound 217: ¹H NMR (CD₃OD, 400 MHz) δ 7.85-7.65 (m, 3H), 7.59-7.55 (m,2H), 7.48-7.45 (m, 1H), 7.17-7.14 (m, 1H), 6.57 (s, 1H), 2.31 (s, 3H),2.13 (s, 3H).

Compound 218: ¹H NMR (CDCl₃, 400 MHz) δ 7.60 (s, 2H), 7.47 (d, J=8.0 Hz,2H), 7.34 (d, J=8.0 Hz, 2H), 7.24 (s, 1H), 6.59 (s, 1H), 2.22 (s, 3H).MS (ESI) m/z (M+H)⁺ 336.0.

Compound 219: ¹H NMR (CDCl₃, 400 MHz) δ 7.58 (s, 2H), 7.16-7.10 (m, 2H),6.84-6.79 (m, 2H), 6.60 (s, 1H), 4.04 (q, J=6.8 Hz, 2H), 2.23 (s, 3H),2.16 (s, 3H), 1.42 (t, J=6.8 Hz, 3H).

Compound 220: ¹H NMR (CDCl₃, 400 MHz) δ 7.59 (s, 2H), 7.26 (s, 2H), 6.60(s, 3H), 3.86 (s, 9H), 2.23 (s, 3H). MS (ESI) m/z (M+H)⁺ 342.1.

The 4-methyl, 5-(1-Me) pyrazole analogs were prepared following the sameprocedure for obtaining XXXVI-3 using1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole inplace of XXXVI-2.

Compound 221: ¹H NMR (CDCl₃, 400 MHz) δ 7.50 (s, 1H), 7.26 (s, 1H),6.59-6.55 (m, 4H), 3.86 (s, 12H), 2.30 (s, 3H). MS (ESI) m/z (M+H)⁺356.0.

Compound 226: ¹H NMR (CD₃OD, 400 MHz) δ 7.81-7.71 (m, 5H), 7.59-7.57 (m,2H), 6.57 (s, 1H), 3.91 (s, 3H), 2.31 (s, 3H). MS (ESI) m/z (M+H)⁺334.1.

Compound 227: ¹H NMR (CD₃OD, 400 MHz) δ 7.51-7.47 (m, 2H), 7.38-7.37 (m,2H), 7.30-7.25 (m, 2H), 7.21 (s, 1H), 6.56 (s, 1H), 3.94 (s, 3H), 2.22(s, 3H). MS (ESI) m/z (M+H)⁺ 350.1.

Compound 228: ¹H NMR (CD₃OD, 400 MHz) δ 7.86-7.84 (m, 2H), 7.71 (s, 1H),7.67-7.65 (m, 2H), 7.61-7.58 (m, 2H), 6.58 (s, 1H), 3.92 (s, 3H), 2.31(s, 3H). MS (ESI) m/z (M+H)⁺ 334.1.

Compounds 225, 229 and 230 were prepared following Method 1 as describedin Example 12-B.

Compound 225: ¹H NMR (CD₃OD, 400 MHz) δ 9.08 (s, 1H), 8.13 (d, J=2.0 Hz,1H), 8.08-8.04 (m, 1H), 7.58-7.55 (m, 1H), 7.50 (s, 1H), 7.39 (s, 1H),7.33 (s, 1H), 6.61 (s, 1H), 3.94 (s, 3H), 2.25 (s, 3H). MS (ESI) m/z(M+H)⁺ 322.9.

Compound 229: ¹H NMR (CDCl₃, 400 MHz) δ 7.45 (s, 1H), 7.36-7.32 (m, 2H),7.28-7.25 (m, 1H), 7.14 (d, J=8.0 Hz, 1H), 7.05 (s, 1H), 6.57 (s, 1H),3.93 (s, 3H), 2.23 (s, 3H), 2.16 (s, 3H). MS (ESI) m/z (M+Na)⁺ 314.1.

Compound 230: ¹H NMR (CDCl₃, 400 MHz) δ 7.47 (s, 1H), 7.46-7.37 (m, 3H),7.28-7.23 (m, 1H), 7.15 (s, 1H), 6.58 (s, 1H), 3.93 (s, 3H), 2.22 (s,3H). MS (ESI) m/z (M+Na)⁺283.9.

Compound 222 was prepared following a modified Method 1 procedure, usingDMSO in place of DCM and the molecular sieve was not used. ¹H NMR(CDCl₃, 300 MHz) δ 7.45 (s, 1H), 7.34 (s, 1H), 7.19 (s, 1H), 6.94-6.91(m, 2H), 6.85-6.81 (m, 1H), 6.50 (s, 1H), 4.26 (s, 4H), 3.92 (s, 3H),2.19 (s, 3H). MS (ESI) m/z [M+H]⁺ 324.

Compounds 223 and 224 were prepared following the similar procedure asdescribed in the synthesis of Compound 222. Compound 223: ¹H NMR (CDCl₃,300 MHz) δ 7.40 (s, 1H), 7.29 (s, 1H), 7.14 (s, 1H), 6.83-6.79 (m, 2H),6.74-6.71 (m, 1H), 6.48 (s, 1H), 5.96 (s, 2H), 3.87 (s, 3H), 2.15 (s,3H). MS (ESI) m/z [M+H]⁺ 310.0. Compound 224: ¹H NMR (CDCl₃, 400 MHz) δ8.17 (s, 1H) 7.81 (s, 1H), 7.70-7.67 (d, J=8.8 Hz, 1H), 7.48-7.45 (m,2H), 7.38 (s, 1H), 7.28 (s, 1H), 6.59 (s, 1H), 3.94 (s, 3H), 2.24 (s,3H). MS (ESI) m/z [M+H]⁺ 307.1.

Compounds 231 and 232 were prepared following Method 3 as described inExample 12-B.

Compound 231: ¹H NMR (CDCl₃, 400 MHz) δ 8.06 (s, 1H), 7.57 (s, 1H), 7.43(s, 1H), 6.87-6.72 (m, 4H), 4.28-4.22 (m, 4H), 3.96 (s, 1H), 2.37 (s,3H). MS (ESI) m/z [M+H]⁺ 323.9.

Compound 232: ¹H NMR (CDCl₃, 400 MHz) δ 7.47 (s, 1H), 7.36 (s, 1H), 7.21(s, 1H), 6.93-6.85 (m, 3H), 6.57 (s, 1H), 6.04 (s, 2H), 3.94 (s, 3H),2.21 (s, 3H). MS (ESI) m/z [M+H]⁺ 309.8.

Compound 431 was prepared following the similar procedure for obtainingXXXVI-3 using Pd-118 and K₃PO₄ instead of Pd(dppf)Cl₂ and K₂CO₃. The Bocprotecting group was subsequently removed in HCl/MeOH solution at rt. ¹HNMR (CDCl₃, 400 MHz) δ 7.59 (s, 2H), 7.47-7.45 (m, 2H), 7.38-7.35 (m,2H), 7.23 (s, 1H), 6.59 (s, 1H), 2.22 (s, 3H). MS (ESI) m/z (M+H)⁺285.9.

Example 13-B Synthesis of Compound 233 (Scheme XXXVII)

A solution of XXXVII-1 (10 g, 53.4 mmol) in HCOOH (50 mL) was heated atreflux for 2 hours, after cooled to rt, aq.NaOH (10%) was added slowlyuntil the mixture was basic. Then extracted with EtOAc (100 mL×3), thecombined organic layers were washed with brine, dried over Na₂SO₄, andconcentrated in vacuo to give XXXVII-2 (9 g, 85% yield).

To a solution of XXXVII-2 (5 g, 25.4 mmol) in THF (35 mL) was addedp-T_(S)OH (1.3 g, 7.6 mmol), DHP (35 ml). The reaction mixture wasstirred at 60° C. overnight. The reaction mixture was poured intoice-water, and the aqueous was extracted with EA (50 mL×3), the combinedorganic layers were washed with brine, dried over Na₂SO₄, andconcentrated in vacuo to give crude XXXVII-3 (4.8 g, 67% yield).

To a solution of XXXVII-3 (1 g, 3.5 mmol) in dioxane (20 mL) was addedKOAc (0.69 g, 7 mmol), bis(pinacolato)diboron (0.95 g 3.67 mmol),Pd(dppf)Cl₂ (0.25 g, 0.035 mmol) under N₂ protection. The reactionmixture was degassed with nitrogen, and then heated to reflux overnight.The reaction mixture was poured into ice-water, and the aqueous wasextracted with EA (60 mL×3), the combined organic layers were washedwith brine, dried over Na₂SO₄, and concentrated in vacuo to give crudeXXXVII-4 (0.8 g, 70% yield).

XXXVII-6 was prepared following the procedure described in the synthesisof Compound 222. MS (ESI) m/z [M+H]⁺ 390.1.

XXXVII-6 (200 mg, 0.5 mmol) was dissolved in a solution of HCl/dioxane(4 M, 50 mL), the mixture was stirred overnight at rt, the mixture wasconcentrated to yield the hydrochloride salt Compound 233a (120 mg, 79%yield). ¹H NMR (DMSO-d₆, 400 MHz) δ 9.66 (s, 1H), 7.99-7.94 (m, 2H),7.90 (s, 1H), 7.64-7.60 (m, 3H), 6.48 (s, 1H), 3.84 (s, 3H), 2.55 (s,3H). MS (ESI) m/z [M+H]⁺ 305.9.

Compound 235 was prepared from Compound 122 following the similarprocedure for obtaining Compound 199. ¹HNMR (CD₃OD, 400 MHz) δ 7.76 (s,1H), 7.59-7.54 (m, 4H), 7.48 (d, J=8.4 Hz, 2H), 6.58 (s, 1H), 3.94 (s,3H), 2.65 (q, J=7.6 Hz, 2H), 1.19 (t, J=7.6 Hz, 3H). MS (ESI) m/z (M+H)⁺364.0.

Example 13-C Synthesis of Compound 236 (Scheme XXXVIII)

To a stirred mixture of Compound 122 (200 mg, 0.54 mmol), XXXVIII-2 (270mg, 0.81 mmol), and K₃CO₃ (150 mg, 1.08 mmol) in toluene (6 mL) wasadded Pd(PPh₃)₄ (60 mg, 0.054 mmol). The mixture was purged withnitrogen for three times and then heated at 120° C. overnight. Themixture was concentrated to remove solvent, diluted with H₂O (10 mL),extracted with EtOAc (20 mL×3). The combined organic layer was washedwith brine, dried over anhydrous Na₂SO₄, and concentrated in vacuo. Thecrude product was purified by prep-HPLC to give XXXVIII-3 (130 mg, 64%yield).

A mixture of XXXVIII-3 (130 mg, 0.259 mmol) and Pd/C in ethanol (5 mL)was stirred under H₂ at rt for 1 hour. Filtered the mixture, andconcentrated to give Compound 236 (86.2 mg, 66% yield). ¹H NMR (CDCl₃,400 MHz) δ 7.48-7.45 (m, 3H), 7.36-7.31 (m, 3H), 7.17 (s, 1H), 6.63 (s,1H), 3.95 (s, 3H), 2.97-2.90 (m, 1H), 1.17 (d, J=6.8 Hz, 6H). MS (ESI)m/z (M+H)⁺ 378.1.

Example 13-D Synthesis of Compound 238 (Scheme XXXIX)

To a stirred mixture of XXXIX-1 (400 mg, 2.4 mmol), XXXIX-2 (500 mg,2.18 mmol), and K₃PO₄ (2 M, 1.1 mL, 2.2 mmol) in dioxane (20 mL) wasadded Pd(dppf)Cl₂ (160 mg, 0.218 mmol) under N₂ protection. The reactionmixture was degassed with nitrogen again and stirred at 90° C.overnight. The mixture was concentrated, diluted with H₂O (20 mL),extracted with EtOAc (30 mL×3). The combined organic layer was washedwith brine, dried over anhydrous Na₂SO₄, and concentrated in vacuo. Theresidue was purified by column chromatography (PE/EA=2/1) to giveXXXIX-3 (400 mg, 67% yield).

A mixture of XXXIX-3 (400 mg, 1.48 mmol) in aq. HBr (40%, 10 mL) andHOAc (5 mL) was stirred at 90° C. for 12 hrs. After being cooled to rt,the mixture was poured into water (20 mL), neutralized with Na₂CO₃, andthen extracted with DCM/i-PrOH (30 mL×3, v/v=9/1). The combined organiclayer was washed with brine, dried over anhydrous Na₂SO₄, andconcentrated in vacuo to afford crude XXXIX-4 (220 mg, 58% yield) aslight yellow oil. MS (ESI) m/z (M+H)⁺257.9.

Compound 238 was prepared following the general procedure described inMethod 1 as pale yellow solid (80 mg, 24% yield). ¹H NMR (CDCl₃, 400MHz) δ 7.46-7.40 (m, 3H), 7.34-7.30 (m, 2H), 7.19 (s, 1H), 6.56 (s, 1H),3.99 (s, 3H), 2.05 (s, 3H). MS (ESI) m/z (M+H)⁺418.0.

Compound 237 was prepared following the similar procedure for obtainingCompound 238 using (1,3,5-trimethyl-1H-pyrazol-4-yl)boronic acid inplace of XXXIX-1 and 5-bromo-2-methoxy-4-methylpyridine in place ofXXXIX-2. ¹H NMR (CDCl₃, 400 MHz) δ 7.45-7.41 (m, 2H), 7.31-7.26 (m, 2H),7.04 (s, 1H), 6.54 (s, 1H), 3.73 (s, 3H), 2.09 (s, 3H), 2.07 (s, 3H),1.96 (s, 3H). MS (ESI) m/z [M+H]⁺ 378.2.

Compound 239 was prepared following the similar procedure for obtainingCompound 238 using (4-ethoxy-2-methylphenyl)boronic acid in place ofXXXIX-5 as a pale yellow solid. ¹H NMR (CDCl₃, 400 MHz) δ 7.40 (s, 1H),7.10-7.05 (m, 2H), 6.85-6.75 (m, 2H), 6.55 (s, 1H), 4.02 (q, J=6.8 Hz,2H), 3.97 (s, 3H), 2.11 (s, 3H), 2.04 (s, 3H), 1.40 (t, J=6.8 Hz, 3H).MS (ESI) m/z (M+H)⁺ 392.1.

Example 13-E Synthesis of Compound 234 (Scheme XL)

XL-6 was prepared following the synthesis scheme described herewith.

To a solution of XL-6 (100 mg, 0.34 mmol) in acetone (10 mL) was addedcompound 2-iodopropane (83.7 mg, 0.51 mmol), and K₂CO₃ (84 mg, 0.68mmol). The reaction mixture was heated to reflux overnight. Aftercooling to rt, the mixture was poured into ice-water, extracted with EA(50 mL×3). The combined organic layer was washed with brine andconcentrated to give crude product. The residue was purified byprep-HPLC to give Compound 234 (50 mg, 44% yield) as a white solid. ¹HNMR (CDCl₃, 400 MHz) δ 7.46 (s, 1H), 7.35 (s, 1H), 6.98 (s, 1H),7.10-7.07 (m, 2H), 6.8 (s, 1H), 6.78-6.76 (m, 1H), 6.56 (s, 1H),4.57-4.51 (m, 1H), 3.92 (s, 3H), 2.23 (s, 3H), 2.13 (s, 3H), 1.34 (d,J=6 Hz, 6H). MS (ESI) m/z [M+H]⁺ 337.9.

Compound 240 was prepared following the similar procedure for obtainingCompound 234 using 5-bromo-4-(trifluoromethyl)pyridin-2(1H)-one in placeof XL-1 and (4-(trifluoromethoxy)phenyl)boronic acid in place of XL-2.¹H NMR (CDCl₃, 400 MHz) δ 7.48-7.46 (m, 3H), 7.42 (s, 1H), 7.38-7.25 (m,3H), 7.07 (s, 1H), 3.94 (s, 3H). MS (ESI) m/z [M+H]⁺ 403.9.

Example 14-A Synthesis of Compound 243 (Scheme XLI)

A solution of LDA (1 M in THF, 10 mL, 10 mmol) was added dropwise to asolution of XLI-1 (0.8 g, 10 mmol) and (n-Bu)₃SnCl (3.7 g, 11 mmol) inTHF (10 mL) at −70° C. under N₂. The reaction mixture was stirred at−70° C. for 1 hour. The reaction was quenched with saturated aq. NH₄Cl(50 mL) and extracted with EA (50 mL×3), the organic layer dried overNa₂SO₄, and concentrated under reduced pressure. The residue waspurified by column chromatography on silica gel (PE/EA=1/1) to giveXLI-2 (1 g, 27% yield).

To a mixture of XLI-3 (0.2 g, 0.58 mmol) and XLI-2 (0.43 g, 1.2 mmol) indioxane (20 mL) was added Pd(PPh₃)₂Cl₂ (0.04 g, 0.058 mmol) under N₂ atrt. The mixture was stirred at reflux overnight. The mixture was dilutedwith water (20 mL) and extracted with CH₂Cl₂ (30 mL×3). The combinedorganic layer was washed with brine, dried over Na₂SO₄, and concentratedunder reduced pressure. The residue was purified by columnchromatography on silica gel (eluted with EA) to afford Compound 243(0.16 g, 80% yield). ¹H NMR (CDCl₃, 400 MHz) δ 9.25-9.20 (m, 2H),7.47-7.33 (m, 3H), 7.38-7.34 (m, 2H), 7.31 (s, 1H), 6.65 (s, 1H), 2.23(s, 3H). MS (ESI) m/z (M+H)+348.0.

Compound 241: To a stirred mixture of XLI-3 (300 mg, 0.86 mmol),pyridin-3-ylboronic acid (160 mg, 1.04 mmol), and K₃PO₄ (0.86 ml, 1.72mmol) in DMF (10 mL) was added Pd(PPh₃)₄ (100 mg, 0.086 mmol) under N₂protection. The reaction mixture was stirred at 110° C. overnight. Themixture was concentrated, diluted with H₂O, extracted with EtOAc (30mL×3), the organic layer was washed with brine, dried over anhydrousNa₂SO₄, and concentrated in vacuo, the residue was purified by prep-HPLCto give Compound 241 (122 mg, 41% yield) as a white solid. ¹H NMR(DMSO-d₆, 400 MHz) δ 8.63 (s, 1H), 8.57-8.56 (m, 1H), 7.90-7.85 (m, 1H),7.70-7.64 (m, 3H), 7.53-7.51 (m, 2H), 7.48-7.45 (m, 1H), 6.52 (s, 1H),2.14 (s, 3H). MS (ESI) m/z [M+H]⁺ 347.1.

Compound 242 was prepared follow the similar procedure for obtainingCompound 241 using pyridin-4-ylboronic acid in place ofpyridin-3-ylboronic acid. ¹H NMR (DMSO-d₆, 400 MHz) δ 8.60 (d, J=4.8 Hz,2H), 7.71 (s, 1H), 7.66-7.64 (m, 2H), 7.53-7.47 (m, 4H), 6.52 (s, 1H),2.19 (s, 3H). MS (ESI) m/z [M+H]⁺ 347.1.

Compound 247 was prepared according to Method 4: To a solution of XLI-3(900 mg, 2.59 mmol) in dioxane/H₂O (12 mL, v/v=5/1) was added K₂CO₃ (720mg, 5.18 mmol),1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(600 mg, 2.85 mmol), Pd(dppf)Cl₂ (180 mg, 0.26 mmol). The mixture waspurged with nitrogen and then heated at 100° C. by microwave for 40 min.The mixture was cooled to rt, diluted with water, extracted with EtOAc(30 mL×3). The combined organic layer was washed with brine, dried overanhydrous Na₂SO₄, and concentrated in vacuo. The residue was purified byflash chromatography on silica gel (PE: EA=10:1→1:1) to give Compound247 as a yellow solid (175 mg, 20% yield). ¹H NMR (CDCl₃, 400 MHz) δ7.53 (s, 1H), 7.48-7.45 (m, 2H), 7.36-7.32 (m, 2H), 7.26 (m, 1H), 6.60(s, 1H), 6.23 (s, 1H), 3.76 (s, 3H), 2.03 (s, 3H).

Compound 254 was prepared following the similar procedure for obtainingXL-5 using5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazole in placeof XL-4 and using 5-XLI-3 in place of XL-3 as a white solid. ¹H NMR(CDCl₃, 400 MHz) δ 8.16 (s, 1H), 7.71 (s, 1H), 7.63 (d, J=8.4 Hz, 1H),7.52-7.48 (m, 2H), 7.35-7.29 (m, 3H), 7.25 (d, J=8.4 Hz, 1H), 6.61 (s,1H), 2.15 (s, 3H). MS (ESI) m/z (M+H)⁺ 387.0.

Compound 255 was prepared following the similar procedure for obtainingCompound 254 using (1-methyl-1H-indol-5-yl)boronic acid and Na₂CO₃instead of K₂CO₃ as a yellow solid. ¹H NMR (DMSO-d₆, 400 MHz) δ7.65-7.63 (m, 2H), 7.54-7.45 (m, 5H), 7.35 (d, J=2.8 Hz, 1H), 7.16 (dd,J=1.6, 8.4 Hz, 2H), 6.47 (s, 1H), 6.20 (d, J=2.8 Hz, 1H), 3.81 (s, 3H),2.13 (s, 3H).

Compound 259 was prepared following the similar procedure for obtainingCompound 255 using5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[c][1,2,5]oxadiazole.¹H NMR (CDCl₃, 400 MHz) δ 7.90 (dd, J=1.2, 9.6 Hz, 1H), 7.75 (s, 1H),7.50-7.48 (m, 2H), 7.39-7.34 (m, 4H), 6.64 (s, 1H), 2.22 (s, 3H).

Compound 251 was prepared following the similar procedure for obtainingCompound 255 using5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazole. ¹H NMR(CDCl₃, 400 MHz) δ 9.06 (s, 1H), 8.06 (s, 1H), 8.01 (d, J=8.4 Hz, 1H),7.52-7.49 (m, 2H), 7.39-7.32 (m, 3H), 7.27 (d, J=8.4 Hz, 1H), 6.63 (s,1H), 2.19 (s, 3H).

Compound 244 was prepared following the similar procedure for obtainingXL-3 by reacting 5-(1H-imidazol-1-yl)-4-methylpyridin-2(1H)-one with(4-(trifluoromethoxy)phenyl) boronic acid. ¹H NMR (CDCl₃, 400 MHz) δ7.60 (s, 1H), 7.57-7.50 (m, 4H), 7.37-7.33 (m, 2H), 7.25 (m, 1H), 6.58(s, 1H), 2.01 (s, 1H). MS (ESI) m/z (M+H)⁺ 336.1.

Compound 245 was prepared following the similar procedure for obtainingXL-5 by reacting XLI-3 with1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole. ¹HNMR (CDCl₃, 400 MHz) δ 7.99 (s, 1H), 7.62 (s, 1H), 7.51 (d, J=9.2 Hz,2H), 7.45 (d, J=8.8 Hz, 1H), 7.34-7.23 (m, 4H), 6.61 (s, 1H), 4.11 (s,3H), 2.15 (s, 3H). MS (ESI) m/z [M+H]⁺ 400.1.

Compound 246 was prepared following the similar procedure for obtainingXL-5 by reacting XLI-3 with2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole. ¹HNMR (CDCl₃, 400 MHz) δ 7.97 (s, 1H), 7.80 (d, J=8.8 Hz, 1H), 7.56 (s,1H), 7.51 (d, J=9.2 Hz, 2H), 7.36 (m, 3H), 7.25 (m, 1H), 6.81 (s, 1H),4.29 (s, 3H). 2.22 (s, 3H). MS (ESI) m/z [M+H]⁺ 400.1

Compound 249 was prepared following the similar procedure for obtainingXL-5 by reacting XLI-3 with1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole. ¹HNMR (CDCl₃, 400 MHz) δ 8.02 (s, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.52-7.50(m, 2H), 7.35-7.33 (m, 2H), 7.29-7.28 (m, 2H), 7.07 (d, J=8.0 Hz, 1H),6.62 (s, 1H), 4.09 (s, 3H), 2.18 (s, 3H). MS (ESI) m/z (M+H)⁺ 400.0.

Compound 250 prepared following the similar procedure for obtaining XL-5by reacting XLI-3 with2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole. ¹HNMR (CDCl₃, 400 MHz) δ 7.94 (s, 1H), 7.68 (d, J=8.0 Hz, 1H), 7.58 (s,1H), 7.53-7.50 (m, 2H), 7.34-7.32 (m, 2H), 7.27 (m, 1H), 7.00 (d, J=8.0Hz, 1H), 6.61 (s, 1H), 4.25 (s, 3H), 2.19 (s, 3H). MS (ESI) m/z (M+H)⁺400.0.

Compound 258 was prepared following the similar procedure for obtainingXL-5 using1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole inplace of XL-4 and using XLI-3 in place of XL-3 as a yellow solid. ¹H NMR(DMSO-d₆, 400 MHz) δ 7.66-7.62 (m, 1H), 7.56-7.48 (m, 4H), 7.44 (s, 1H),7.33 (s, 1H), 7.02 (d, J=8.0 Hz, 1H), 6.48 (s, 1H), 6.42 (m, 1H), 3.78(s, 3H), 2.15 (s, 3H). MS (ESI) m/z (M+H)⁺ 398.9.

Compound 260 was prepared following the similar procedure for obtainingXL-5 using6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazole in placeof XL-4 and using XLI-3 in place of XL-3. ¹H NMR (CDCl₃, 400 MHz) δ 9.05(s, 1H), 8.17 (d, J=8.4 Hz, 1H), 7.88 (s, 1H), 7.52-7.43 (m, 3H),7.37-7.32 (m, 2H), 7.28-7.26 (m, 1H), 6.63 (s, 1H), 2.19 (s, 3H). MS(ESI) m/z (M+H)⁺ 403.0.

Compound 432 was prepared following the similar procedure for obtainingcompound 243 using Pd-118 and K₃PO₄ instead of Pd(dppf)Cl₂ and K₂CO₃. ¹HNMR (CDCl₃, 400 MHz) δ 9.25 (d, J=5.2 Hz, 1H), 9.20 (s, 1H), 7.50-7.47(m, 2H), 7.44-7.42 (m, 1H), 7.38-7.35 (m, 2H), 7.30 (s, 1H), 6.64 (s,1H), 2.22 (s, 3H). MS (ESI) m/z (M+H)⁺ 297.9.

Example 14-B Synthesis of Compound 248 (Scheme XLII)

A flask was charged with XLI-3 (0.8 g, 2.30 mmol, 1 eq), XLII-2 (1.02 g,4.60 mmol, 2 eq), Pd(dppf)Cl₂—CH₂Cl₂ (0.094 g, 0.11 mmol, 0.05 eq),K₃PO₄ (1.22 g, 4.60 mmol, 2 eq) and 50 mL of dioxane, flushed withnitrogen for three times. The mixture was heated at 80° C. for 8 hrs.LCMS analysis showed the reaction completed. The reaction mixture wascooled down to rt, diluted with water, extracted with ethyl acetate (80mL×3). The combined organic layer was washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated to give brown oil.Recrystallization from EA gave offwhite solid XLII-3 (0.4 g, 48% yield).MS (ESI) m/z (M+H)⁺362.9.

A flask was charged with XLII-3 (300 mg, 0.83 mmol, 1 eq), NaHCO₃ (139mg, 1.66 mmol, 2 eq), aq. 2-chloroacetaldehyde (40%, 1.6 g, 8.3 mmol, 10eq) and 20 mL of EtOH. The mixture was heated to reflux for 18 hrs. LCMSanalysis showed the reaction completed. The reaction mixture was cooleddown to rt, diluted with water, extracted with ethyl acetate (50 mL×3).The combined organic layer was washed with brine, dried over anhydroussodium sulfate, filtered and concentrated to give a brown oil.Purification by prep-TLC (PE/EA=2/1) gave Compound 248 as a brown solid(145.5 mg, 45% yield). MS (ESI) m/z (M+H)⁺ 386.9. ¹H NMR (DMSO-d₆, 400MHz) δ 9.05 (d, J=2.4 Hz, 1H), 8.64 (d, J=2.4 Hz, 1H), 7.90 (s, 1H),7.84 (s, 1H), 7.76 (s, 1H), 7.66 (d, J=8.4 Hz, 2H), 7.54 (d, J=8.4 Hz,2H), 6.55 (s, 1H), 2.22 (s, 3H).

Compound 252 was prepared following the similar procedure for obtainingCompound 248 using5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine in placeof XLII-2. MS (ESI) m/z (M+H)⁺ 386.9. ¹H NMR (DMSO-d₆, 300 MHz): δ 8.62(s, 1H), 7.92 (s, 1H), 7.72 (s, 1H), 7.66-7.53 (m, 6H), 7.33 (d, J=6.8Hz, 1H), 6.52 (s, 1H), 2.19 (s, 3H).

Example 14-C Synthesis of Compound 253, 256 and 257 (Scheme XLIII)

To the solution of XLIII-1 (600 mg, 1.7 mmol) in 5 mL of NMP was addedCuCN (462 mg, 5.1 mmol). The mixture was heated to 180° C. for 3 hrs.The mixture was diluted with H₂O, extracted with EtOAc (50 mL×3). Thecombined organic layer was washed with brine, dried over anhydrousNa₂SO₄, and concentrated in vacuo, the residue was purified by columnchromatography on silica gel (PE/EA=5/1) to give XLIII-2 (400 mg, 80%yield) as a white solid.

To the solution of XLIII-2 (300 mg, 1 mmol) in 3 mL of DMF was addedNaN₃ (130 mg, 2 mmol). and Cu(OAc)₂ (360 mg, 2 mmol). The mixture washeated to 100° C. under microwave for 20 minutes. And then the mixturewas filtered at 70° C., the filtrate was cooled to rt, the mixture wasfiltered again. The residual solid was dissolved in HCl/MeOH (4 M),stirred at rt for 1 h. The mixture was concentrated to give Compound 253(50 mg, 14.5% yield) as black solid. ¹H NMR (DMSO-d₆, 400 MHz) δ 8.17(s, 1H), 7.60 (m, 2H), 7.51 (m, 2H), 6.51 (s, 1H), 2.36 (s, 3H). MS(ESI) m/z (M+H)⁺ 338.0.

To the solution of Compound 253 (200 mg, 0.59 mmol) in 2 mL of DMF wasadded CH₃I (100 mg, 0.7 mmol). and K₂CO₃ (170 mg, 1.2 mmol). The mixturewas stirred at rt for 3 hrs. The mixture was diluted with H₂O, extractedwith EtOAc (50 mL×3). The combined organic layer was washed with brine,dried over anhydrous Na₂SO₄, and concentrated in vacuo, the residue waspurified by prep-TLC (PE/EA=1/1) to give Compound 256 (130 mg, 62%yield) and Compound 257 (40 mg, 19% yield). ¹H NMR (CDCl₃, 400 MHz) δ8.15 (s, 1H), 7.50 (d, J=8.8 Hz, 2H), 7.36 (d, J=8.8 Hz, 2H), 6.60 (s,1H), 4.38 (s, 3H), 2.55 (s, 3H). MS (ESI) m/z (M+H)⁺351.9. ¹H NMR(CDCl₃, 400 MHz) δ 7.48-7.44 (m, 3H), 7.35 (d, J=8.8 Hz, 2H), 6.65 (s,1H), 4.05 (s, 3H), 2.13 (s, 3H). MS (ESI) m/z (M+H)⁺ 351.9.

Compounds 261-264 were also prepared following the general procedure asdescribed herein.

Compound 261: ¹H NMR (CDCl₃, 400 MHz) δ 9.04 (s, 1H), 8.03-8.00 (m, 1H),7.53-7.47 (m, 3H), 7.42-7.28 (m, 4H), 6.65 (s, 1H), 2.07 (s, 3H). MS(ESI) m/z [M+H]⁺ 402.8.

Compound 262: MS (ESI) m/z [M+H]⁺ 352.8. ¹H NMR (CDCl₃, 400 MHz) δ 8.87(m, 1H), 7.70 (s, 1H), 7.51-7.47 (m, 2H), 7.35-7.27 (m, 3H), 6.60 (s,1H), 2.36 (s, 3H).

Compound 263: ¹H NMR (DMSO-d₆, 400 MHz) δ 9.42 (s, 1H), 8.10 (d, J=8.0Hz, 1H), 7.78 (s, 1H), 7.64-7.59 (m, 3H), 7.51-7.45 (m, 3H), 6.55 (s,1H), 1.98 (s, 3H). MS (ESI) m/z [M+H]⁺ 402.9.

Compound 264: ¹H NMR (CDCl₃, 400 MHz) δ 8.54 (s, 1H), 8.48 (s, 1H),7.49-7.45 (m, 2H), 7.37-7.32 (m, 2H), 7.29 (s, 1H), 6.61 (s, 1H), 2.19(s, 3H). MS (ESI) m/z [M+H]⁺ 353.1.

Example 15 5-Bromo Pyridone Analogs

Compounds 265-273 were prepared following Method 1 in Example 12-B using5-bromopyridin-2(1H)-one reacting with the relevant boronic acids.

Compound 265: ¹HNMR (DMSO-d₆, 400 MHz) δ 7.97 (s, 1H), 7.63 (d, J=9.6Hz, 1H), 7.52-7.48 (m, 2H), 7.37-7.32 (m, 2H), 6.48 (d, J=9.6 Hz, 1H).MS (ESI) m/z (M+H)⁺268.1.

Compound 266: ¹HNMR (DMSO-d₆, 400 MHz) δ 8.34 (s, 1H), 8.02 (d, J=9.6Hz, 1H), 7.85-7.81 (m, 1H), 7.46-7.38 (m, 3H), 6.88 (d, J=9.6 Hz, 1H),4.21 (s, 3H). MS (ESI) m/z (M+H)⁺ 280.0.

Compound 267: ¹HNMR (DMSO-d₆, 400 MHz) δ 7.92 (d, J=2.8 Hz, 1H), 7.60(dd, J=9.6, 2.8 Hz, 1H), 7.32-7.29 (m, 2H), 7.02-6.99 (m, 2H), 6.45 (d,J=9.6 Hz, 1H), 4.70-4.63 (m, 1H), 1.32 (d, J=6.0 Hz, 6H). MS (ESI) m/z(M+H)⁺ 310.0.

Compound 268: ¹HNMR (DMSO-d₆, 400 MHz) δ 8.07 (d, J=2.8 Hz, 1H), 7.91(s, 1H), 7.85-7.82 (m, 1H), 7.80-7.73 (m, 2H), 7.65 (dd, J=9.6, 2.8 Hz,1H), 6.51 (d, J=9.6 Hz, 1H). MS (ESI) m/z (M+H)⁺ 319.9.

Compound 269: ¹HNMR (DMSO-d₆, 400 MHz) δ 7.98 (d, J=2.8 Hz, 1H), 7.63(dd, J=9.6, 2.8 Hz, 1H), 7.60-7.56 (m, 2H), 7.50-7.47 (m, 2H), 6.48 (d,J=9.6 Hz, 1H). MS (ESI) m/z (M+H)⁺ 285.8.

Compound 270: ¹HNMR (DMSO-d₆, 400 MHz) δ 8.03 (d, J=2.8 Hz, 1H),7.66-7.59 (m, 3H), 7.53-7.50 (m, 2H), 6.50 (d, J=10 Hz, 1H). MS (ESI)m/z (M+H)⁺ 335.9.

Compound 271: ¹HNMR (DMSO-d₆, 400 MHz) δ 10.17 (s, 1H), 7.96 (d, J=2.8Hz, 1H), 7.70 (s, 1H), 7.67-7.58 (m, 2H), 7.44 (t, J=8.0 Hz, 1H),7.10-7.07 (m, 1H), 6.49 (d, J=10 Hz, 1H), 2.07 (s, 3H). MS (ESI) m/z(M+Na)⁺ 328.9.

Compound 272: ¹HNMR (DMSO-d₆, 400 MHz) δ 7.98 (d, J=2.8 Hz, 1H), 7.62(dd, J=9.6, 2.8 Hz, 1H), 7.58-7.50 (m, 1H), 7.42-7.39 (m, 1H), 7.33-7.27(m, 2H), 6.47 (d, J=9.6 Hz, 1H). MS (ESI) m/z (M+H)⁺ 267.8.

Compound 273: ¹HNMR (DMSO-d₆, 400 MHz) δ 7.83 (d, J=2.8 Hz, 1H), 7.63(dd, J=9.6, 2.8 Hz, 1H), 7.15 (d, J=8.4 Hz, 1H), 6.93 (d, J=2.8 Hz, 1H),6.86-6.83 (m, 1H), 6.47 (d, J=9.6 Hz, 1H), 4.07 (q, J=6.8 Hz, 2H), 2.01(s, 3H), 1.35 (t, J=6.8 Hz, 3H). MS (ESI) m/z (M+H)⁺ 307.9.

Example 16 5-substituted Pyridone Analogs

Compounds 274-278, 280 and 281 were prepared following Method 1 inExample 12-B by reacting 5-trifluoromethyl pyridin-2(1H)-one reactingwith the relevant boronic acids.

Compound 274: ¹H NMR (CDCl₃, 400 MHz) δ 7.73 (s, 1H), 7.58-7.49 (m, 2H),7.22-7.15 (m, 3H), 6.74 (d, J=9.6 Hz, 1H). MS (ESI) m/z (M+H)⁺ 257.9.

Compound 275: ¹H NMR (CDCl₃, 400 MHz) δ 7.73 (s, 1H), 7.54 (d, J=9.6 Hz,1H), 7.48-7.42 (m, 2H), 7.38-7.36 (m, 2H), 6.73 (d, J=9.6 Hz, 1H). MS(ESI) m/z (M+H)⁺ 324.1.

Compound 276: ¹H NMR (CDCl₃, 400 MHz) δ 7.74 (s, 1H), 7.54-7.50 (m, 1H),7.45-7.40 (m, 1H), 7.03-6.99 (m, 1H), 6.94-6.90 (m, 2H), 6.72 (d, J=9.6Hz, 1H), 3.85 (s, 3H). MS (ESI) m/z (M+H)⁺ 270.1.

Compound 277: ¹HNMR (DMSO-d₆, 400 MHz) δ 10.18 (s, 1H), 8.25 (s, 1H),7.79-7.75 (m, 1H), 7.71 (s, 1H), 7.63-7.61 (m, 1H), 7.48-7.43 (m, 1H),7.14-7.11 (m, 1H), 6.66 (d, J=9.6 Hz, 1H), 2.07 (s, 3H). MS (ESI) m/z(M+H)⁺ 296.9.

Compound 278: ¹HNMR (DMSO-d₆, 400 MHz) δ 8.13 (m, 1H), 7.76-7.72 (m,1H), 7.18 (d, J=8.4 Hz, 1H), 6.91 (s, 1H), 6.84-6.81 (m, 1H), 6.61 (d,J=9.6 Hz, 1H), 4.04 (q, J=6.8 Hz, 2H), 1.97 (s, 3H), 1.31 (t, J=6.8 Hz,3H). MS (ESI) m/z (M+H)⁺ 298.1.

Compound 280: ¹H NMR: (CDCl₃, 400 MHz) δ 7.67 (s, 1H), 7.55-7.48 (m,2H), 7.40-7.35 (m, 1H), 7.32-7.28 (m, 2H), 6.75 (d, J=9.6 Hz, 1H). MS(ESI) m/z (M+H)⁺ 258.1.

Compound 281: ¹H NMR: (CDCl₃, 400 MHz) δ 7.61-7.53 (m, 3H), 7.47-7.37(m, 3H), 6.76 (d, J=9.6 Hz, 1H). MS (ESI) m/z (M+H)⁺ 273.9.

Compound 279 were prepared following Method 2 in Example 12-B byreacting 5-trifluoromethyl pyridin-2(1H)-one with 5-bromopyridine. ¹HNMR (CDCl₃, 400 MHz) δ 9.31 (s, 1H), 8.89 (s, 2H), 7.72 (s, 1H), 7.59(d, J=9.6 Hz, 1H), 6.78 (d, J=9.6 Hz, 1H). MS (ESI) m/z (M+H)⁺ 242.0.

Compound 282 was prepared following Method 1 in Example 12-B by reacting5-methyl pyridine-2(1H)-one with (3,4,5-triflurophenyl)boronic acid. ¹HNMR (CDCl₃, 300 MHz) δ 7.28 (d, J=2.4 Hz, 1H), 7.10-7.03 (m, 3H), 6.59(d, J=9.6 Hz, 1H), 2.10 (s, 3H). MS (ESI) m/z (M+H)⁺ 239.9.

Compound 283 was prepared following Method 2 by reacting 5-methylpyridine-2(1H)-one with 1-fluoro-2-iodobenzene. ¹H NMR (DMSO-d₆, 300MHz) δ 7.42-7.31 (m, 2H), 7.30-7.21 (m, 3H), 7.01 (s, 1H), 6.62 (d,J=9.6 Hz, 1H), 2.09 (s, 3H). MS (ESI) m/z (M+H)⁺ 204.1.

Compound 285 was prepared following the general methods describedherein. ¹H NMR (CDCl₃, 400 MHz) δ 7.50-7.47 (m, 2H), 7.43-7.35 (m, 4H),7.10 (d, J=2.4 Hz, 1H), 6.64 (d, J=9.6 Hz, 1H), 2.73-2.65 (m, 1H), 1.20(d, J=6.8 Hz, 6H). MS (ESI) m/z (M+H)⁺ 214.2.

Compound 287: To a mixture of 5-bromo-1-phenylpyridin-2(1H)-one (0.25 g,1 mmol) and ethynyltrimethylsilane (5 mL) in DMF (10 mL) and TEA (2 mL)was added CuI (0.02 g, 0.1 mmol) and Pd(PPh₃)₂Cl₂ (0.07 g, 0.1 mmol).The mixture was purged with nitrogen for 5 minutes and stirred under N₂at 100° C. overnight. The reaction mixture was worked up to afford anintermediate product (0.16 g, 60% yield), which was mixed with TBAF(0.16 g, 0.6 mmol) in CH₂Cl₂ (5 mL) was stirred at rt for 3 hours. Theorganic layer was concentrated and the residue was purified by columnchromatography (PE/EA=10/1) to yield Compound 287 (0.08 g, 68% yield).¹H NMR (CDCl₃, 400 MHz) δ 7.6 (d, J=2.4 Hz, 1H), 7.54-7.35 (m, 6H), 6.63(d, J=9.6 Hz, 1H), 3.03 (s, 1H). MS (ESI) m/z (M+H)⁺ 196.1.

Example 17 5-Phenyl Pyridone Analogs

Compounds 288 through 331 were prepared following the similar proceduresdescribed herein in Method A through C and Method 1 through 4.

Compound 288: ¹H NMR (DMSO-d₆, 400 MHz) δ 7.91-7.87 (m, 2H), 7.68-7.64(m, 2H), 7.37 (d, J=8.8 Hz, 2H), 7.22 (t, J=8.8 Hz, 2H), 7.02 (d, J=8.8Hz, 2H), 6.57 (d, J=9.2 Hz, 1H), 4.70-4.64 (m, 1H), 1.30 (d, J=6.0 Hz,6H). MS (ESI) m/z [M+H]⁺ 324.1.

Compound 289: ¹H NMR (DMSO-d₆, 400 MHz) δ 8.05 (d, J=2.4 Hz, 1H),7.96-7.93 (m, 2H), 7.86-7.84 (m, 2H), 7.79-7.77 (m, 1H), 7.72-7.68 (m,2H), 7.24 (t, J=8.8 Hz, 2H), 6.62 (d, J=9.6 Hz, 1H). MS (ESI) m/z [M+H]⁺333.9.

Compound 290: ¹H NMR (DMSO-d₆, 400 MHz) δ 8.02-7.94 (m, 2H), 7.69-7.66(m, 2H), 7.61-7.53 (m, 2H), 7.46-7.37 (m, 2H), 7.36-7.22 (m, 2H), 6.62(d, J=9.6 Hz, 1H). MS (ESI) m/z [M+H]⁺ 284.0.

Compound 291: ¹H NMR (CDCl₃, 400 MHz) δ 7.69 (dd, J=2.4, 9.6 Hz, 1H),7.61-7.58 (m, 1H), 7.48-7.35 (m, 6H), 7.08 (t, J=8.4 Hz, 2H), 6.78 (d,J=9.6 Hz, 1H). MS (ESI) m/z [M+H]⁺ 300.1.

Compound 294: ¹H NMR (CDCl₃, 400 MHz): δ 7.72-7.70 (m, 1H), 7.53 (s,1H), 7.46-7.39 (m, 6H), 7.37-7.32 (m, 1H), 7.22-7.17 (m, 2H), 6.74 (d,J=9.6 Hz, 1H). MS (ESI) m/z (M+H)⁺ 266.0.

Compound 295: ¹H NMR (CDCl₃, 400 MHz) δ 7.73-7.70 (m, 1H), 7.57 (s, 1H),7.46-7.39 (m, 5H), 7.36-7.32 (m, 1H), 7.02-6.97 (m, 3H), 6.75 (d, J=9.6Hz, 1H), 3.84 (s, 3H). MS (ESI) m/z (M+H)⁺ 277.9.

Compound 296: ¹H NMR (CDCl₃, 400 MHz): δ 7.73-7.70 (m, 1H), 7.52-7.40(m, 6H), 7.36-7.32 (m, 1H), 7.24-7.14 (m, 3H), 6.75 (d, J=9.6 Hz, 1H).MS (ESI) m/z (M+H)⁺ 266.1.

Compound 297: ¹H NMR (CDCl₃, 400 MHz): δ 7.76-7.65 (m, 5H), 7.55 (s,1H), 7.46-7.40 (m, 4H), 7.38-7.32 (m, 1H), 6.77 (d, J=9.6 Hz, 1H). MS(ESI) m/z (M+H)⁺ 315.2.

Compound 298: ¹H NMR (CDCl₃, 400 MHz): δ 7.76-7.73 (m, 1H), 7.47-7.40(m, 5H), 7.35-7.31 (m, 1H), 7.15 (d, J=8.4 Hz, 1H), 6.88-6.82 (m, 2H),6.77 (d, J=9.2 Hz, 1H), 4.06 (q, J=6.8 Hz, 2H), 2.17 (s, 3H), 1.44 (t,J=6.8 Hz, 3H). MS (ESI) m/z (M+H)⁺ 305.9.

Compound 308: ¹H NMR (CDCl₃, 400 MHz) δ 7.69-7.66 (m, 1H), 7.49-7.45 (m,2H), 7.35 (d, J=8 Hz, 2H), 7.25-7.15 (m, 3H), 6.97-6.93 (m, 2H), 6.75(d, J=9.6 Hz, 1H), 3.83 (s, 3H). MS (ESI) m/z (M+H)⁺ 296.0.

Compound 309: ¹H NMR (CDCl₃, 400 MHz) δ 7.68-7.65 (m, 1H), 7.35 (d,J=2.4 Hz, 1H), 7.43-7.33 (m, 3H), 7.01-6.93 (m, 5H), 6.75 (d, J=9.2 Hz,1H), 3.83 (s, 6H). MS (ESI) m/z (M+H)⁺ 308.0.

Compound 310: ¹H NMR (CDCl₃, 300 MHz) δ 7.72-7.69 (m, 1H), 7.60-7.57 (m,1H), 7.43-7.41 (m, 3H), 7.37-7.33 (m, 3H), 6.96-6.93 (m, 2H), 6.77 (d,J=9.6 Hz, 1H), 3.83 (s, 3H). MS (ESI) m/z (M+H)⁺ 311.9.

Compound 314: ¹H NMR (CDCl₃, 400 MHz) δ 7.68 (dd, J=2.8, 9.6 Hz, 1H),7.52-7.49 (m, 3H), 7.41-7.29 (m, 6H), 6.75 (d, J=9.6 Hz, 1H). MS (ESI)m/z (M+H)⁺ 315.9.

Compound 315: ¹H NMR (CDCl₃, 400 MHz) δ 7.68-7.65 (m, 1H), 7.56 (d,J=4.0 Hz, 1H), 7.42-7.28 (m, 6H), 7.04-7.00 (m, 2H), 6.76 (d, J=9.2 Hz,1H), 3.86 (s, 3H). MS (ESI) m/z (M+H)⁺ 312.0.

Compound 316: ¹H NMR: (CDCl₃, 400 MHz) δ 7.67-7.64 (m, 1H), 7.56 (s,1H), 7.42 (s, 1H), 7.34-7.28 (m, 5H), 7.00-6.97 (m, 2H), 6.76 (d, J=9.2Hz, 1H), 4.63-4.55 (m, 1H), 1.38 (s, 3H), 1.36 (s, 3H). MS (ESI) m/z(M+H)⁺ 340.1.

Compound 317: ¹H NMR: (DMSO-d₆, 400 MHz) δ 8.09 (m, 1H), 7.96 (dd,J=2.8, 9.6 Hz, 1H), 7.75 (s, 1H), 7.62-7.53 (m, 3H), 7.43-7.33 (m, 4H),6.59 (d, J=9.6 Hz, 1H). MS (ESI) m/z (M+H)⁺ 299.9.

Compound 318: ¹H NMR: (CDCl₃, 400 MHz) δ 7.73-7.66 (m, 5H), 7.54 (s,1H), 7.43-7.30 (m, 4H), 6.78 (d, J=9.6 Hz, 1H). MS (ESI) m/z (M+H)⁺349.9.

Compound 319: ¹H NMR: (CDCl₃, 400 MHz) δ 7.68-7.65 (m, 1H), 7.56 (s,1H), 7.43-7.39 (m, 2H), 7.34-7.28 (m, 3H), 7.01-6.96 (m, 3H), 6.75 (d,J=9.6 Hz, 1H), 3.84 (s, 3H). MS (ESI) m/z (M+H)⁺ 311.9.

Compound 320: ¹H NMR: (CDCl₃, 400 MHz) δ 8.11 (s, 1H), 7.97-7.94 (m,1H), 7.78 (s, 1H), 7.61-7.32 (m, 7H), 6.60 (d, J=9.6 Hz, 1H). MS (ESI)m/z (M+H)⁺ 299.9

Compound 321: ¹H NMR: (CDCl₃, 400 MHz) δ 7.42 (d, J=4.0 Hz, 1H),7.43-7.38 (m, 2H), 7.29-7.27 (m, 3H), 7.12 (d, J=8.0 Hz, 1H), 6.84-6.80(m, 2H), 6.75 (d, J=9.6 Hz, 1H), 4.03 (q, J=6.8 Hz, 2H), 2.13 (s, 3H),1.41 (t, J=6.8 Hz, 3H). MS (ESI) m/z (M+H)⁺ 340.1

Compound 322: ¹H NMR: (CDCl₃, 400 MHz) δ 7.73-7.69 (m, 1H), 7.60-7.58(m, 1H), 7.46-7.29 (m, 8H), 6.79 (d, J=9.6 Hz, 1H). MS (ESI) m/z (M+H)⁺316.0.

Compound 292: ¹H NMR (CDCl₃, 400 MHz) δ 8.36-8.31 (m, 2H), 7.86-7.85 (m,1H), 7.74-7.68 (m, 2H), 7.50 (s, 1H), 7.42-7.38 (m, 2H), 7.15-7.11 (m,2H), 6.78 (d, J=9.2 Hz, 1H). MS (ESI) m/z [M+H]⁺ 310.8.

Compound 299: ¹HNMR (CDCl₃, 400 MHz) δ 8.77 (brs, 2H), 7.73-7.68 (m,1H), 7.51-7.32 (m, 8H), 6.77-6.72 (m, 1H). MS (ESI) m/z (M+H)⁺ 249.2.

Compound 302: ¹HNMR (CDCl₃, 400 MHz) δ 7.78-7.75 (m, 1H), 7.62-7.58 (m,1H), 7.47-7.40 (m, 8H), 7.35-7.32 (m, 1H), 6.79 (d, J=9.6 Hz, 1H). MS(ESI) m/z (M+H)⁺ 282.2.

Compound 300: ¹HNMR (CDCl₃, 400 MHz) δ 9.27 (s, 1H), 8.95 (s, 2H),7.80-7.75 (m, 1H), 7.51-7.35 (m, 6H), 6.79 (d, J=9.6 Hz, 1H). MS (ESI)m/z (M+H)⁺ 250.0.

Compound 301: ¹HNMR (CDCl₃, 400 MHz) δ 7.76-7.72 (m, 1H), 7.50-7.39 (m,7H), 7.38-7.27 (m, 3H), 6.78 (d, J=9.6 Hz, 1H). MS (ESI) m/z (M+H)⁺265.9.

Compound 311: ¹H NMR (CDCl₃, 400 MHz) δ 9.26 (s, 1H), 8.94 (s, 2H), 7.72(dd, J=2.8, 9.6 Hz, 1H), 7.41 (d, J=2.0 Hz, 1H), 7.35-7.33 (m, 2H),6.97-6.95 (m, 2H), 6.77 (d, J=9.6 Hz, 1H), 3.84 (s, 3H). MS (ESI) m/z(M+H)⁺ 279.9.

Compound 323: ¹H NMR: (CDCl₃, 400 MHz) δ 8.82 (brs, 2H), 7.72-7.68 (m,1H), 7.52 (d, J=2.4 Hz, 1H), 7.47-7.42 (m, 2H), 7.39-7.30 (m, 4H), 6.79(d, J=9.6 Hz, 1H). MS (ESI) m/z (M+H)⁺ 283.1.

Compound 312: ¹H NMR (CDCl₃, 400 MHz) δ 7.71-7.68 (m, 1H), 7.48-7.39 (m,3H), 7.37-7.27 (m, 4H), 6.96-6.93 (m, 2H), 6.76 (d, J=9.6 Hz, 1H), 3.83(s, 3H). MS (ESI) m/z (M+H)⁺ 296.0.

Compound 324: ¹H NMR: (CDCl₃, 400 MHz) δ 7.70-7.67 (m, 1H), 7.48-7.41(m, 4H), 7.37-7.28 (m, 5H), 6.79 (d, J=9.6 Hz, 1H). MS (ESI) m/z (M+H)⁺300.1.

Compound 303: ¹HNMR (DMSO-d₆, 400 MHz) δ 7.90-7.86 (m, 2H), 7.59-7.51(m, 6H), 6.97-6.94 (m, 2H), 6.59 (d, J=9.6 Hz, 1H), 3.76 (s, 3H). MS(ESI) m/z z (M+H)⁺ 312.0.

Compound 304: ¹HNMR (DMSO-d₆, 400 MHz) δ 7.95-7.76 (m, 6H), 7.59-7.54(m, 2H), 6.98-6.95 (m, 2H), 6.60 (d, J=9.6 Hz, 1H), 3.76 (s, 3H). MS(ESI) m/z (M+H)⁺ 345.9.

Compound 305: ¹HNMR (DMSO-d₆, 400 MHz) δ 7.89-7.82 (m, 2H), 7.66-7.54(m, 4H), 7.43-7.39 (m, 2H), 7.08-7.03 (m, 2H), 6.98-6.96 (m, 2H), 6.56(d, J=9.2 Hz, 1H), 3.82 (s, 3H), 3.77 (s, 3H). MS (ESI) m/z (M+H)⁺308.0.

Compound 306: ¹HNMR (DMSO-d₆, 400 MHz) δ 7.91-7.87 (m, 2H), 7.59-7.53(m, 4H), 7.39-7.33 (m, 2H), 6.99-6.96 (m, 2H), 6.59 (d, J=9.2 Hz, 1H),3.78 (s, 3H). MS (ESI) m/z (M+H)⁺ 296.1.

Compound 307: ¹HNMR (DMSO-d₆, 400 MHz) δ 7.88-7.82 (m, 2H), 7.56-7.54(m, 2H), 7.39-7.36 (m, 2H), 7.04-6.95 (m, 4H), 6.56 (d, J=9.2 Hz, 1H),4.71-4.66 (m, 1H), 3.78 (s, 3H), 1.31 (d, J=6.0 Hz, 6H). MS (ESI) m/z(M+H)⁺ 336.1.

Compound 313: ¹H NMR (CDCl₃, 400 MHz) δ 7.69-7.66 (m, 1H), 7.58-7.51 (m,3H), 7.49-7.42 (m, 4H), 7.36-7.29 (m, 3H), 6.77 (d, J=9.6 Hz, 1H). MS(ESI) m/z (M+H)⁺ 281.9.

Compound 293: ¹H NMR (DMSO-d₆, 400 MHz) δ 7.90-7.87 (m, 2H), 7.68-7.64(m, 2H), 7.26-7.13 (m, 3H), 6.65-6.54 (m, 4H), 5.40 (brs, 2H). MS (ESI)m/z [M+H]⁺ 280.9.

Compound 325: ¹H NMR (DMSO-d₆, 400 MHz) δ 8.13 (d, J=2.8 Hz, 1H),8.02-7.99 (m, 1H), 7.86-7.81 (m, 4H), 7.60-7.56 (m, 2H), 7.40-7.35 (m,4H), 6.64 (d, J=9.6 Hz, 1H). MS (ESI) m/z (M+H)⁺ 344.9.

Compound 326: ¹H NMR (DMSO-d₆, 400 MHz) δ 7.88 (d, J=2.4 Hz, 1H),7.75-7.72 (m, 1H), 7.60-7.54 (m, 4H), 7.34-7.29 (m, 1H), 7.25-7.22 (m,1H), 7.13-7.05 (m, 4H), 6.37 (d, J=9.6 Hz, 1H). MS (ESI) m/z (M+H)⁺345.2.

Compound 327: ¹H NMR (DMSO-d₆, 400 MHz) δ 8.15 (d, J=2.8 Hz, 1H),8.04-8.01 (m, 1H), 7.87-7.82 (m, 4H), 7.64-7.57 (m, 4H), 7.38 (s, 2H),6.65 (d, J=9.6 Hz, 1H). MS (ESI) m/z (M+H)⁺ 360.9.

Compound 328: ¹H NMR (DMSO-d₆, 400 MHz) δ 8.09 (d, J=2.8 Hz, 1H),8.00-7.97 (m, 1H), 7.85-7.80 (m, 4H), 7.44-7.41 (m, 2H), 7.37 (s, 2H),7.08-7.02 (m, 2H), 6.62 (d, J=9.6 Hz, 1H), 3.82 (s, 3H). MS (ESI) m/z(M+H)⁺ 356.9.

Compound 329: ¹HNMR (DMSO-d₆, 400 MHz) δ 8.21 (s, 1H), 8.02 (dd, J=2.4,9.6 Hz, 1H), 7.96 (s, 1H), 7.87-7.65 (m, 7H), 7.40 (s, 2H), 6.65 (d,J=9.6 Hz, 1H). MS (ESI) m/z (M+H)⁺ 394.9.

Compound 330: ¹H NMR (DMSO-d₆, 400 MHz) δ 8.08 (d, J=2.8 Hz, 1H),7.98-7.95 (m, 1H), 7.84-7.76 (m, 4H), 7.39-7.36 (m, 4H), 7.02 (d, J=8.8Hz, 2H), 6.60 (d, J=9.6 Hz, 1H), 4.70-4.64 (m, 1H), 1.29 (d, J=6.0 Hz,6H). MS (ESI) m/z (M+H)⁺ 384.8.

Compound 331: ¹H NMR (DMSO-d₆, 400 MHz) δ 8.11 (d, J=2.4 Hz, 1H),8.03-8.00 (m, 1H), 7.87-7.81 (m, 4H), 7.49-7.42 (m, 1H), 7.39 (s, 2H),7.11-7.04 (m, 3H), 6.63 (d, J=9.6 Hz, 1H), 3.81 (s, 3H). MS (ESI) m/z(M+H)⁺ 356.9.

Example 18 2(1H)-Thione Analogs

Compounds 332-339 and 341-343 were prepared according to the generalprocedure: To a solution of Pirfenidone analog (1 eq.) in toluene wasadded Lawesson reagent (0.6 eq.). The reaction mixture was refluxedunder nitrogen overnight. After being cooled to rt, the mixture wasconcentrated under reduced pressure. The residue was purified by flashchromatography on silica gel (eluenting with petroleum ether/EtOAc) toprovide final thione analogs.

Compound 332: ¹H NMR (DMSO-d₆, 400 MHz) δ 7.83 (s, 1H), 7.47-7.44 (m,1H), 7.32-7.25 (m, 3H), 7.08-7.04 (m, 2H), 3.82 (s, 3H), 2.13 (s, 3H).MS (ESI) m/z (M+H)⁺ 231.9.

Compound 333: ¹H NMR (CDCl₃, 300 MHz) δ 7.67 (d, J=8.7 Hz, 1H),7.41-7.38 (m, 5H), 7.15 (d, J=9.0 Hz, 1H), 2.17 (s, 3H). MS (ESI) m/z(M+H)⁺ 285.9.

Compound 334: ¹H NMR (CDCl₃, 300 MHz) δ 7.67 (d, J=9.0 Hz, 1H), 7.41 (s,1H), 7.25-7.20 (m, 2H), 7.09 (d, J=9.0 Hz, 1H), 6.96 (d, J=9.0 Hz, 2H),4.60-4.52 (m, 1H), 2.15 (s, 3H), 1.35 (d, J=6.0 Hz, 6H). MS (ESI) m/z(M+H)⁺ 259.9.

Compound 335: ¹H NMR (CDCl₃, 300 MHz) δ 7.68 (d, J=9.0 Hz, 1H),7.51-7.47 (m, 2H), 7.37 (s, 1H), 7.30 (d, J=1.8 Hz, 1H), 7.28 (s, 1H),7.12 (dd, J=2.1, 9.0 Hz, 1H), 2.18 (s, 3H). MS (ESI) m/z (M+H)⁺ 236.2.

Compound 336: ¹H NMR (CDCl₃, 300 MHz) δ 7.67 (d, J=9.0 Hz, 1H), 7.39 (s,1H), 7.37-7.10 (m, 5H), 2.17 (s, 3H). MS (ESI) m/z (M+H)⁺ 219.9.

Compound 337: ¹H NMR (CDCl₃, 400 MHz) δ 7.75-7.57 (m, 5H), 7.37 (s, 1H),7.13 (d, J=8.8 Hz, 1H), 2.17 (s, 3H). MS (ESI) m/z (M+H)⁺ 270.0.

Compound 338: ¹H NMR (CDCl₃, 300 MHz) δ 7.67 (d, J=9.0 Hz, 1H),7.53-7.48 (m, 1H), 7.39 (s, 1H), 7.21-7.08 (m, 4H), 2.17 (s, 3H). MS(ESI) m/z (M+H)⁺ 219.9.

Compound 339: ¹H NMR (CDCl₃, 300 MHz) δ 7.67 (d, J=9.0 Hz, 1H),7.42-7.40 (m, 2H), 7.11 (d, J=8.7 Hz, 1H), 7.01 (d, J=8.7 Hz, 1H), 6.90(d, J=9.0 Hz, 1H), 6.86-6.84 (m, 1H), 3.82 (s, 3H), 2.17 (s, 3H). MS(ESI) m/z (M+H)⁺ 231.9.

Compound 341: ¹H NMR (DMSO-d₆, 400 MHz) δ 7.84 (s, 1H), 7.69-7.67 (m,1H), 7.54-7.38 (m, 4H), 7.37 (dd, J=2.0, 9.2 Hz, 1H), 2.14 (s, 3H). MS(ESI) m/z (M+H)⁺ 236.1.

Compound 342: ¹H NMR (DMSO-d₆, 400 MHz) δ 7.73 (s, 1H), 7.44 (d, J=8.8Hz, 1H), 7.30 (dd, J=2.0, 8.8 Hz, 1H), 7.04 (d, J=8.4 Hz, 1H), 6.91 (d,J=2.8 Hz, 1H), 6.84 (dd, J=2.8, 8.4 Hz, 1H), 4.04 (q, J=6.8 Hz, 2H),2.11 (s, 3H), 1.94 (s, 3H), 1.33 (t, J=6.8 Hz, 3H). MS (ESI) m/z (M+H)⁺260.1.

Compound 343: ¹H NMR (DMSO-d₆, 400 MHz) δ 10.17 (s, 1H), 7.83 (s, 1H),7.63 (d, J=1.6 Hz, 1H), 7.54 (d, J=8.0 Hz, 1H), 7.45-7.41 (m, 2H), 7.31(dd, J=2.0, 8.8 Hz, 1H), 6.96 (t, J=6.4 Hz, 1H), 2.11 (s, 3H), 2.05 (s,3H). MS (ESI) m/z (M+H)⁺ 258.9.

Example 19 5-Heterocycle Substituted Analogs

Compounds 344-346 were prepared following the similar procedure inScheme XXVIII, Method 1.

Compound 344: ¹H NMR (DMSO-d₆, 400 MHz) δ 9.11-9.09 (m, 3H), 8.26 (m,1H), 8.05-8.02 (m, 1H), 7.58-7.55 (m, 2H), 7.39-7.35 (m, 2H), 6.64 (d,J=9.6 Hz, 1H). MS (ESI) m/z (M+H)⁺ 267.8.

Compound 345: ¹H NMR (DMSO-d₆, 400 MHz) δ 9.13 (m, 3H), 8.31 (m, 1H),8.08-8.05 (m, 1H), 7.61-7.57 (m, 1H), 7.54-7.50 (m, 1H), 7.42-7.36 (m,2H), 6.68 (d, J=9.6 Hz, 1H). MS (ESI) m/z (M+H)⁺ 267.7.

Compound 346: ¹H NMR (CDCl₃, 400 MHz) δ 9.20 (s, 1H), 8.86 (s, 2H),7.70-7.67 (m, 1H), 7.54 (d, J=2.4 Hz, 1H), 7.52-7.43 (m, 2H), 7.34-7.29(m, 2H), 6.86 (d, J=9.6 Hz, 1H). MS (ESI) m/z (M+H)⁺ 289.9.

Compound 347 was prepared following the similar synthetic procedure forobtaining Compound 243: ¹H NMR (CDCl₃, 400 MHz) δ 9.34 (d, J=2.4 Hz,1H), 9.20 (d, J=5.6 Hz, 1H), 7.79-7.74 (m, 2H), 7.52-7.49 (m, 2H),7.41-7.39 (m, 2H), 6.85 (d, J=9.6 Hz, 1H). MS (ESI) m/z (M+H)⁺ 334.9.

Compound 348 was prepared following the similar procedure in SchemeXXVIII, Method 1, except that the first step intermediate was formed byreacting imidazole with 5-bromo-2-methoxypyridine in DMSO with thepresence of L-proline, CuI, K₂CO₃ and 4 Å molecular sieve. ¹H NMR (400MHz, CDCl₃) δ 7.69 (s, 1H), 7.53-7.47 (m, 4H), 7.39-7.36 (m, 2H), 7.21(s, 1H), 7.11 (s, 1H), 6.78 (d, J=8.0 Hz, 1H). MS (ESI) m/z (M+H)⁺321.9.

Example 20 3-Methyl Substituted Analogs (Scheme XLIV)

To a solution of NaOMe (5.29 g, 98 mmol) in MeOH (500 mL) was addedXLIV-1 (10 g, 49 mmol) by portionwise. The reaction mixture was heatedto reflux overnight. The solution was cooled, quenched with waterslowly, extracted with PE (100 mL×3). The combined organic layer waswashed with brine and concentrated to give XLIV-2 (8.0 g, 81% yield) asa white solid.

XLIV-5 was prepared following the similar procedure in Method 1 forobtaining XXVIII-5. ¹H NMR (CDCl₃, 300 MHz) δ 7.51-7.35 (m, 7H), 2.19(s, 3H). MS (ESI) m/z [M+H]⁺ 265.8.

Compounds 349, 351 and 353 were prepared by reacting XLIV-5 with therelevant boronic acid or ester following the similar procedure describedin Method A.

Compound 349: ¹H NMR (CDCl₃, 400 MHz) δ 7.68-7.52 (m, 2H), 7.48-7.35 (m,3H), 7.20-7.16 (m, 1H), 6.96 (s, 1H), 2.17 (s, 3H), 2.08 (s, 3H). MS(ESI) m/z [M+H]⁺ 200.0.

Compound 351: ¹H NMR (DMSO-d₆, 300 MHz) δ 7.80 (m, 2H), 7.78-7.62 (m,2H), 7.52-7.44 (m, 5H), 7.23-7.17 (m, 2H), 2.09 (s, 3H). MS (ESI) m/z[M+H]⁺ 280.1.

Compound 353: ¹H NMR (DMSO-d₆, 300 MHz) δ 7.99 (s, 1H), 7.74-7.68 (m,3H), 7.49-7.39 (m, 5H), 3.78 (s, 3H), 2.06 (s, 3H). MS (ESI) m/z [M+H]⁺265.9.

Compound 350: To a mixture of5-bromo-3-methyl-1-(4-(trifluoromethoxy)phenyl)pyridin-2(1H)-one (300mg, 0.86 mmol, 1 eq.) in 12 mL of toluene/EtOH/H₂O (v/v/v=4/1/1) wereadded (4-fluorophenyl)boronic acid (242 mg, 1.73 mmol, 2 eq.) and K₂CO₃(357 mg, 2.59 mmol, 3 eq.). The mixture was degassed by N₂ for threetimes and then Pd(PPh₃)₄ (100 mg, 0.08 mmol, 0.1 eq.) was added. Thereaction vessel was sealed and heated in microwave at 100° C. for 1 h.After being cooled to rt, the mixture was diluted with EA (100 mL),washed with water and brine, dried over anhydrous Na₂SO₄ andconcentrated. The resulting residue was purified by prep-TLC (PE/EA=3/2)to afford Compound 350 (210 mg, 67% yield) as a white solid. ¹H NMR(CDCl₃, 400 MHz) δ 7.55 (s, 1H), 7.51-7.47 (m, 2H), 7.41-7.34 (m, 5H),7.11 (t, J=8.8 Hz, 2H), 2.27 (s, 3H). MS (ESI) m/z [M+H]⁺ 364.0.

Compound 352 was prepared by following the similar procedure forobtaining Compound 350 using1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole inplace of (4-fluorophenyl)boronic acid as a white solid. ¹H NMR (CDCl₃,400 MHz) δ 7.58 (s, 1H), 7.48-7.43 (m, 4H), 7.36-7.32 (m, 3H), 3.93 (s,3H), 2.24 (s, 3H). MS (ESI) m/z [M+H]⁺ 350.1.

Example 21 Pirfenidone Analogs with Heterocyclic Core

Compound 354 was prepared following the similar procedure described inMethod 1 by reacting isoquinolin-3(2H)-one with phenyl boronic acid. ¹HNMR (DMSO-d₆, 400 MHz) δ 8.75 (s, 1H), 7.60-7.50 (m, 6H), 7.35-7.28 (m,2H), 6.92-6.88 (m, 1H), 6.59 (s, 1H). MS (ESI) m/z (M+H)⁺ 222.0.

Compounds 355 and 356 were prepared following the similar proceduredescribed in Scheme XXVII and Method A using 5-bromopyrimidin-2(1H)-onein place of XXVII-1 and Pd(PPh₃)₄ in place of Pd(dppf)Cl₂.

Compound 355: ¹H NMR (CDCl₃, 400 MHz) δ 8.83 (d, J=3.6 Hz, 1H), 7.77 (d,J=3.6 Hz, 1H), 7.61 (s, 1H), 7.56-7.44 (m, 6H), 3.96 (s, 3H). MS (ESI)m/z [M+H]⁺ 253.0.

Compound 356: ¹H NMR (CDCl₃, 400 MHz) δ 8.95 (d, J=3.2 Hz, 1H), 7.85 (d,J=3.6 Hz, 1H), 7.57-7.40 (m, 7H), 7.17 (t, J=8.4 Hz, 2H). MS (ESI) m/z[M+H]⁺ 267.0.

Compound 357 was prepared following the similar procedure described inScheme XXVIII and Method A using 5-bromo-2-methoxypyrimidine in place ofXXVIII-1 and Pd(PPh₃)₄ in place of Pd(dppf)Cl₂ ¹H NMR (DMSO-d₆, 400 MHz)δ 9.11 (d, J=2.8 Hz, 1H), 8.58 (d, J=3.6 Hz, 1H), 7.79-7.74 (m, 4H),7.58 (d, J=8.4 Hz, 2H), 7.30 (t, J=8.4 Hz, 2H).

Compound 358 was prepared following the general procedure described inMethod 1 by reacting 5-methylpyrimidin-2(1H)-one with phenyl boronicacid. ¹H NMR (CDCl₃, 400 MHz) δ 8.60 (brs, 1H), 7.52-7.40 (m, 6H), 2.16(s, 3H). MS (ESI) m/z [M+H]⁺ 187.1.

Compounds 359 and 360 were prepared following the general proceduredescribed in Method 1 by reacting 6-methylpyridazin-3(2H)-one with therelevant boronic acid.

Compound 359: ¹H NMR (CDCl₃, 300 MHz) δ 7.58 (d, J=7.8 Hz, 2H),7.49-7.44 (m, 2H), 7.39-7.34 (m, 1H), 7.11 (d, J=9.6 Hz, 1H), 6.68 (d,J=9.3 Hz, 1H), 2.38 (s, 3H). MS (ESI) m/z [M+H]⁺ 187.1.

Compound 360: ¹H NMR (DMSO-d₆, 300 MHz) δ 7.66 (d, J=9.0 Hz, 2H),7.47-7.40 (m, 3H), 6.99 (d, J=9.6 Hz, 1H), 2.28 (s, 3H). MS (ESI) m/z[M+H]⁺ 271.1.

Compound 361 was prepared following the general procedure described inMethod A by reacting 6-chloro-2-phenylpyridazin-3(2H)-one with1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. ¹HNMR (DMSO-d₆, 400 MHz) δ 8.25 (s, 1H), 7.90-7.85 (m, 2H), 7.60-7.59 (m,2H), 7.51-7.50 (m, 2H), 7.41 (t, J=7.6 Hz, 1H), 7.11 (d, J=10.0 Hz, 1H),3.86 (s, 3H). MS (ESI) m/z [M+H]⁺ 252.8. Compounds 362 and 363 wereprepared similarly starting with6-chloro-2-(4-(trifluoromethoxy)phenyl)pyridazin-3(2H)-one.

Compound 362: ¹H NMR (CDCl₃, 400 MHz) δ 7.82-7.71 (m, 5H), 7.35 (d,J=8.0 Hz, 2H), 7.18-7.14 (m, 3H). MS (ESI) m/z (M+H)⁺ 351.0.

Compound 363: ¹H NMR (CDCl₃, 400 MHz) δ 7.84 (s, 1H), 7.78 (s, 1H), 7.75(d, J=6.8 Hz, 2H), 7.49 (d, J=10 Hz, 1H), 7.34-7.31 (m, 2H), 7.08 (d,J=9.6 Hz, 1H), 3.96 (s, 3H). MS (ESI) m/z (M+H)⁺ 337.1.

Compound 364 was prepared following the similar procedure for obtainingCompound 355 using (4-(trifluoromethoxy)phenyl)boronic acid in place ofphenyl boronic acid. ¹H NMR (CDCl₃, 400 MHz) δ 8.85 (s, 1H), 7.75 (s,1H), 7.60-7.52 (m, 4H), 7.40-7.35 (m, 2H), 3.97 (s, 3H). MS (ESI) m/z(M+H)⁺ 337.2.

Compound 365: To a solution of 1-phenylpyrimidin-2(1H)-one (250 mg, 1.45mmol) in dry THF (20 mL) was added a solution of NaBH₄ (58 mg, 1.5 mmol)in 20 mL MeOH by dropwise at 0° C. The reaction mixture was stirred atrt for 1 h. The mixture was concentrated to remove DCM, the residue waspurified by SFC to give 1-phenyl-3,4-dihydropyrimidin-2(1H)-one andCompound 365 (74.8 mg, 30% yield) as a white solid. ¹H NMR (CDCl₃, 400MHz) δ 7.41-7.33 (m, 4H), 7.23-7.21 (m, 1H), 6.53 (brs, 1H), 6.14-6.11(m, 1H), 4.88-4.84 (m, 1H), 4.32-4.31 (m, 2H). MS (ESI) m/z [M+H]⁺174.9.

Example 22 4-Methyl Substituted Analogs

Compound 366: To a stirred mixture of5-bromo-4-methyl-1-phenylpyridin-2(1H)-one (300 mg, 1.15 mmol) andPd(dppf)Cl₂ (83 mg, 0.1 mmol) in 10 mL of anhydrous dioxane was addedZn(Me)₂ (1.2 M in toluene, 3.8 mL, 4.56 mmol) under N₂ protection. Thereaction mixture was refluxed overnight. After being cooled to rt, themixture was filtered, concentrated. The resulting residue was dilutedwith H₂O (30 mL), extracted with EtOAc (50 mL×3). The combined organiclayer was washed with brine, dried over anhydrous Na₂SO₄, andconcentrated in vacuo. The residue was purified by prep-TLC (PE/EA=3/1)to produce Compound 366 (60 mg, 26% yield) as a white solid. ¹H NMR(CDCl₃, 400 MHz) δ 7.49-7.45 (m, 2H), 7.41-7.36 (m, 3H), 7.07 (s, 1H),6.49 (s, 1H), 2.18 (s, 3H), 2.03 (s, 3H). MS (ESI) m/z [M+H]⁺ 200.1.

Compound 367 was prepared following the similar procedure for obtainingCompound 366 using5-bromo-4-methyl-1-(4-(trifluoromethoxy)phenyl)pyridin-2(1H)-one insteadof 5-bromo-4-methyl-1-phenylpyridin-2(1H)-one. ¹H NMR (CDCl₃, 400 MHz) δ7.42-7.39 (m, 2H), 7.33-7.30 (m, 2H), 7.03 (s, 1H), 6.48 (s, 1H), 2.17(s, 3H), 2.03 (s, 3H). MS (ESI) m/z (M+H)⁺284.1.

Compound 368 was prepared following the similar procedure described inMethod 1 by reacting 4-methyl-5-(trifluoromethyl)pyridin-2(1H)-one with(4-(trifluoromethoxy)phenyl)boronic acid as a yellow solid. ¹H NMR(CDCl₃, 400 MHz) δ 7.70 (s, 1H), 7.44-7.41 (m, 2H), 7.39-7.36 (m, 2H),6.61 (s, 1H), 2.38 (s, 3H). MS (ESI) m/z (M+H)⁺ 337.9.

Example 23 5-Pyrazole Substituted Analogs (Scheme XLV)

To a mixture of XLV-1 (1 eq.), XLV-2 (1.3 eq.) and K₂CO₃ (2 eq.) inDME/H₂O (v/v=6/1) was added Pd(PPh₃)₄ (0.1 eq.). The reaction mixturewas degassed by purging with nitrogen and then was heated to refluxovernight. After the completion of the reaction, the mixture was cooledto rt, diluted with water and extracted with CH₂Cl₂. The combinedorganic layer was washed with brine, dried over Na₂SO₄, and concentratedunder reduced pressure. The residue was purified by flash chromatographyon silica gel (PE/EA=1/1 to EA) to afford XLV-3. Compounds 369-377 wereprepared following the general procedure discussed above.

Compound 369: ¹H NMR (DMSO-d₆, 400 MHz) δ 12.8 (brs, 1H), 8.09-8.01 (m,1H), 7.90-7.78 (m, 2H), 7.33 (d, J=8.8 Hz, 1H), 7.01 (d, J=8.8 Hz, 1H),6.50 (d, J=9.6 Hz, 1H), 4.68-4.62 (m, 1H), 1.28 (d, J=6.0 Hz, 6H).

Compound 370: ¹H NMR (CDCl₃, 400 MHz) δ 7.67 (s, 2H), 7.58-7.55 (m, 1H),7.48 (s, 1H), 7.33 (d, J=8.8 Hz, 2H), 7.00 (d, J=8.8 Hz, 2H), 6.73 (d,J=9.2 Hz, 1H), 3.85 (s, 3H).

Compound 371: ¹H NMR (DMSO-d₆, 400 MHz) δ 8.10 (brs, 1H), 7.91 (s, 1H),7.86-7.82 (m, 2H), 7.60-7.57 (m, 2H), 7.60-7.57 (m, 2H), 6.54 (d, J=9.2Hz, 1H).

Compound 372: ¹H NMR (DMSO-d₆, 400 MHz) δ 8.11 (brs, 1H), 7.96 (s, 1H),7.89-7.85 (m, 2H), 7.61-7.57 (m, 1H), 7.46 (d, J=8.0 Hz, 1H), 7.37-7.31(m, 2H), 6.58 (d, J=8.0 Hz, 1H).

Compound 373: ¹H NMR (DMSO-d₆, 400 MHz) δ 12.87 (brs, 1H), 8.10 (brs,1H), 7.99 (s, 1H), 7.90-7.77 (m, 6H), 6.58 (d, J=8.4 Hz, 1H).

Compound 374: ¹H NMR (DMSO-d₆, 400 MHz) δ 12.87 (brs, 1H), 8.10 (brs,1H), 7.99 (s, 1H), 7.87 (d, J=8.4 Hz, 2H), 7.63-7.60 (m, 2H), 7.54-7.50(m, 2H), 6.55 (d, J=9.6 Hz, 1H).

Compound 375: ¹H NMR (DMSO-d₆, 400 MHz) δ 12.86 (brs, 1H), 8.10 (brs,1H), 7.90-7.80 (m, 3H), 7.44-7.39 (m, 1H), 7.03-6.98 (m, 3H), 6.53 (d,J=9.2 Hz, 1H), 3.78 (s, 3H).

Compound 376: ¹H NMR (DMSO-d₆, 400 MHz) δ 12.86 (brs, 1H), 8.10 (s, 1H),7.87-7.79 (m, 3H), 7.18 (d, J=8.8 Hz, 1H), 6.95-6.86 (m, 2H), 6.55 (d,J=7.2 Hz, 1H), 4.07 (q, J=6.8 Hz, 2H), 2.03 (s, 3H), 1.35 (t, J=6.8 Hz,3H). MS (ESI) m/z (M+H)⁺ 295.9.

Compound 377: ¹H NMR (DMSO-d₆, 400 MHz) δ 12.86 (brs, 1H), 8.09 (brs,1H), 7.91 (d, J=2.4 Hz, 1H), 7.85-7.82 (m, 2H), 7.53-7.49 (m, 2H),7.37-7.33 (m, 2H), 6.53 (d, J=9.6 Hz, 1H).

Compound 627 was obtained from the corresponding non-Boc protectedboronic ester following the general procedure described in Method A: ¹HNMR (CDCl₃, 400 MHz) δ 7.45-7.39 (m, 3H), 7.37-7.30 (m, 3H), 7.18 (s,1H), 6.51 (s, 1H), 3.91 (s, 3H), 2.19 (s, 3H). MS (ESI) m/z (M+H)⁺300.1.

Compound 628: ¹H NMR (DMSO-d₆, 400 MHz) δ 8.83 (s, 1H), 7.87 (s, 1H),7.57 (s, 1H), 7.55 (m, 1H), 7.46 (s, 1H), 7.34-7.31 (m, 2H), 6.93-6.89(m, 1H), 6.40 (s, 1H), 5.95 (s, 2H), 3.81 (s, 3H), 2.21 (s, 3H). MS(ESI) m/z (M+H)⁺ 324.1.

Compound 385: To a solution of XLV-3a (0.2 g, 0.8 mmol) in CH₃CN (15 mL)was added K₂CO₃ (0.5 g, 3.6 mmol), benzyl chloride (0.37 g, 2.9 mmol).The mixture was purged with nitrogen and then heated to refluxovernight. The mixture was cooled to rt, diluted with water, extractedwith EtOAc (20 mL×3). The combined organic layer was washed with brine,dried over anhydrous Na₂SO₄, and concentrated in vacuo. The residue waspurified by column chromatography on silica gel (PE:EA=1:2) to giveCompound 385 (112.8 mg, 46% yield). ¹H NMR (DMSO-d₆, 400 MHz) δ 8.18 (s,1H), 7.91 (d, J=2.4 Hz, 1H), 7.85 (s, 1H), 7.80 (d, J=8.8 Hz, 1H),7.53-7.42 (m, 5H), 7.33-7.21 (m, 5H), 6.53 (d, J=9.6 Hz, 1H), 5.28 (s,2H). MS (ESI) m/z (M+H)⁺ 328.2.

Compound 388 was prepared following the similar procedure for obtainingCompound 385 using isopropyl iodide in place of benzyl chloride. ¹H NMR(CDCl₃, 400 MHz) δ 7.58-7.50 (m, 5H), 7.47-7.40 (m, 4H), 6.72 (d, J=9.6Hz, 1H), 4.54-4.48 (m, 1H), 1.52 (d, J=6.8 Hz, 6H). MS (ESI) m/z (M+H)⁺280.0.

Compound 389: To a stirred mixture of XLV-3a (0.2 g, 0.8 mmol),iodobenzene (2 g, 9.8 mmol), and K₂CO₃ (0.89 g, 6.4 mmol) in DMF (2 mL)was added CuI (0.12 g, 0.8 mmol). The mixture was purged with nitrogenfor three times and then heated at 140° C. under microwave for 2 hrs.The mixture was diluted with H₂O, extracted with EtOAc (20 mL×3). Thecombined organic layer was washed with water and brine, dried overanhydrous Na₂SO₄, and concentrated in vacuo. The crude product waschromatographed on silica gel (PE: EA=1:2) to give Compound 389 (50.3mg, 25% yield). ¹H NMR (CDCl₃, 400 MHz) δ 8.01 (s, 1H), 7.81 (s, 1H),7.69 (d, J=8.0 Hz, 2H), 7.63-7.60 (m, 1H), 7.55-7.42 (m, 8H), 7.33-7.29(m, 1H), 6.76 (d, J=8.0 Hz, 1H). MS (ESI) m/z (M+H)⁺ 314.2.

Compounds 378, 379, 381, 387 and 390 were prepared following the similarprocedure for obtaining XLV-3 using XLV-2a in place of XLV-2.

Compound 378: ¹H NMR (DMSO-d₆, 400 MHz) δ 12.30 (brs, 1H), 7.54-7.51 (m,1H), 7.44-7.40 (m, 2H), 7.03-7.00 (m, 3H), 6.54 (d, J=9.2, 1H), 3.80 (s,3H), 2.18 (s, 6H). MS (ESI) m/z (M+H)⁺ 295.9.

Compound 379: ¹H NMR (DMSO-d₆, 400 MHz) δ 12.30 (brs, 1H), 7.44-7.36 (m,3H), 7.21-7.17 (m, 3H), 6.72 (d, J=9.6 Hz, 1H), 2.27 (s, 6H).

Compound 381: ¹H NMR (CDCl₃, 400 MHz) δ 7.50-7.43 (m, 1H), 7.40-7.36 (m,1H), 7.23-7.10 (m, 4H), 6.73 (d, J=9.6 Hz, 1H), 2.27 (s, 6H). MS (ESI)m/z (M+H)⁺ 283.1.

Compound 387: ¹H NMR (DMSO-d₆, 400 MHz) δ 7.53 (d, J=9.2 Hz, 1H), 7.32(s, 1H), 7.53 (d, J=8.4 Hz, 1H), 6.94 (s, 1H), 6.87-6.84 (m, 1H), 6.54(d, J=9.2 Hz, 1H), 4.05 (q, J=6.8 Hz, 2H), 2.17 (s, 6H), 2.05 (s, 3H),1.35 (t, J=6.8 Hz, 3H). MS (ESI) m/z (M+H)⁺ 323.4.

Compound 390: ¹H NMR (CDCl₃, 400 MHz) δ 8.79-8.78 (m, 2H), 7.46-7.45 (m,2H), 7.40-7.38 (m, 1H), 7.18 (s, 1H), 6.74 (d, J=9.6 Hz, 1H), 2.28 (s,6H). MS (ESI) m/z (M+H)⁺267.1.

Compound 380 were prepared following the similar procedure for obtainingXLV-3 using XLV-2a in place of XLV-2 and using Pd(dppf)Cl₂ in place ofPd(PPh₃)₄. ¹H NMR (DMSO-d₆, 400 MHz): δ 12.25 (s, 1H), 7.60-7.47 (m,6H), 6.51 (d, J=9.2 Hz, 1H), 2.16 (s, 6H). MS (ESI) m/z (M+H)⁺ 299.8.

Additional Boc-deprotection procedure: To a solution of XLV-4a (1 eq.)in MeOH (0.1-0.2 mmol/mL) was added a solution of HCl (gas) in dioxane(4 M, volume was two times of MeOH). The mixture was stirred at rt for 1h. After the completion of the reaction, the mixture was concentrated invacuo. The crude product was purified by prep-HPLC to yield XLV-5. Thepreparation of Compounds 382-384 and 386 followed the above deprotectionprocedure.

Compound 382: ¹H NMR (DMSO-d₆, 400 MHz) δ 12.28 (s, 1H), 7.50 (dd,J=9.6, 2.8 Hz, 1H), 7.42 (d, J=2.4 Hz, 1H), 7.33 (dd, J=6.8, 2.0 Hz,1H), 7.02 (d, J=9.2 Hz, 1H), 5.52 (d, J=9.2 Hz, 1H), 4.70-4.64 (m, 1H),2.17 (s, 6H), 1.30 (s, 6H).

Compound 383: ¹H NMR (DMSO-d₆, 400 MHz) δ 12.27 (s, 1H), 7.61 (dd,J=6.8, 2.4 Hz, 1H), 7.54-7.50 (m, 5H), 6.55 (dd, J=8.8, 1.2 Hz, 1H),2.16 (s, 6H).

Compound 384: ¹H NMR (DMSO-d₆, 400 MHz) δ 12.27 (s, 1H), 7.88 (s, 1H),7.82-7.73 (m, 3H), 7.55-7.52 (m, 2H), 6.56 (dd, J=8.8, 0.8 Hz, 1H), 2.16(s, 6H).

Compound 386: ¹H NMR (DMSO-d₆, 400 MHz) δ 12.27 (s, 1H), 7.88 (s, 1H),7.49 (dd, J=9.6, 2.8 Hz, 1H), 7.40-7.34 (m, 3H), 7.04-7.02 (m, 2H), 6.50(d, J=9.2 Hz, 1H), 3.79 (s, 3H), 2.15 (s, 6H).

Compound 391 was prepared by following the similar procedure forobtaining Compound 238 (Scheme XXXIX) by using4-bromo-1,5-dimethyl-1H-pyrazole in place of XXXIX-2. ¹H NMR (CDCl₃, 400MHz) δ 7.49-7.42 (m, 4H), 7.38-7.33 (m, 2H), 7.26-7.24 (m, 1H), 6.71 (d,J=9.2 Hz, 1H), 3.83 (s, 3H), 2.32 (s, 3H). MS (ESI) m/z [M+H]⁺ 349.9.

Compounds 420-422 were prepared following Scheme XLV using5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazole or5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazole as XLV-2and 5-bromo-1-(4-ethoxy-2-methylphenyl)-4-methylpyridin-2(1H)-one or5-bromo-1-(4-chlorophenyl)-4-methylpyridin-2(1H)-one as XLV-1.

Compound 420: ¹H NMR (CDCl₃, 400 MHz) δ 8.14 (s, 1H), 7.70 (s, 1H),7.62-7.59 (m, 1H), 7.32-7.30 (m, 1H), 7.15-7.12 (m, 2H), 6.85-6.79 (m,2H), 6.61 (s, 1H), 4.03 (q, J=6.8 Hz, 2H), 2.18 (s, 3H), 2.16 (s, 3H),1.41 (t, J=6.8 Hz, 3H). MS (ESI) m/z (M+H)⁺ 361.1.

Compound 421: ¹H NMR (CDCl₃, 400 MHz) δ 9.07 (s, 1H), 8.05 (s, 1H), 8.00(d, J=8.0 Hz, 1H), 7.48-7.43 (m, 2H), 7.42-7.37 (m, 3H), 7.26 (s, 1H),6.62 (s, 1H), 2.18 (s, 3H). MS (ESI) m/z (M+H)⁺ 352.9.

Compound 422: ¹H NMR (CDCl₃, 400 MHz) δ 8.16 (s, 1H), 7.70 (s, 1H), 7.62(d, J=8.0 Hz, 1H), 7.48-7.43 (m, 2H), 7.41-7.38 (m, 2H), 7.32-7.28 (m,2H), 6.60 (s, 1H), 2.14 (s, 3H). MS (ESI) m/z (M+H)⁺ 337.2.

Example 24 5-Phenyl, 4-Alkyl Substituted Analogs (Scheme XLVI)

XLVI-3 was prepared following the general procedure described inMethod 1. MS (ESI) m/z (M+H)⁺ 325.1.

A mixture of XLVI-3 (2.3 g, 7.08 mmol) and Pd/C (˜0.2 g) in ethanol (30mL) was stirred under H₂ at rt overnight. Filtered the mixture, andconcentrated the filtrate to give XLVI-4 (1.6 g, 77% yield). MS (ESI)m/z (M+H)⁺ 294.9.

To a solution of XLVI-4 (400 mg, 1.36 mmol) in dioxane/H₂O (11 mL,v/v=10:1) was added Na₂CO₃ (288 mg, 2.72 mmol) with stirring at 0° C.Then ethyl chloroformate (XLVI-5) (443 mg, 4.08 mmol) was addeddropwise. The mixture was stirred at rt for 5 hours. The reaction wasevaporated to dryness. The residue was diluted with water (20 mL),extracted with EtOAc (30 mL×3). The combined organic layer was washedwith brine, dried over anhydrous Na₂SO₄ and concentrated. The crude waspurified by prep-TLC (PE/EA=1/1) to give Compound 416 (389 mg, 78%yield) as a white solid. ¹H NMR (DMSO-d₆, 400 MHz) δ 9.81 (s, 1H), 7.54(s, 1H), 7.47-7.34 (m, 5H), 7.24-7.20 (m, 2H), 7.05 (d, J=8.0 Hz, 1H),6.44 (s, 1H), 4.11 (q, J=7.2 Hz, 2H), 2.08 (s, 3H), 1.22 (t, J=7.2 Hz,3H). MS (ESI) m/z [M+H]⁺ 366.9.

Compound 417: To the solution of XLVI-4 (500 mg, 1.7 mmol) in Py (2 mL)was added dimethylcarbamic chloride (365 mg, 3.4 mmol). The mixture wasstirred at rt overnight. The reaction was partitioned between EA (100mL) and H₂O (20 mL). The organic layer was separated, washed with aq.HCl (2N) and brine, dried over anhydrous Na₂SO₄ and concentrated. Theresidue was purified by prep-TLC (PE/EA=1/3) to give Compound 417 (160mg, 26% yield). ¹H NMR (DMSO-d₆, 400 MHz) δ 8.46 (s, 1H), 7.57 (s, 1H),7.53 (d, J=8.4 Hz, 1H), 7.44-7.41 (m, 2H), 7.39 (s, 1H), 7.31 (t, J=8.0Hz, 1H), 7.22 (t, J=8.8 Hz, 2H), 7.00-6.98 (m, 1H), 6.44 (s, 1H), 2.91(s, 6H), 2.09 (s, 3H). MS (ESI) m/z [M+H]⁺ 365.9.

Compound 419: To the solution of XLVI-4 (500 mg, 1.7 mmol) in Py (2 mL)was added methylcarbamic chloride (317 mg, 3.4 mmol). The mixture wasstirred at rt overnight. The reaction was partitioned between EA (100mL) and H₂O (20 mL). The organic layer was separated, washed with aq.HCl (2N) and brine, dried over anhydrous Na₂SO₄ and concentrated. Theresidue was purified by prep-TLC (PE/EA=1/3) to give Compound 419 (209mg, 35% yield). ¹H NMR (DMSO-d₆, 400 MHz) δ 8.73 (s, 1H), 7.57 (s, 1H),7.47-7.42 (m, 3H), 7.38-7.30 (m, 2H), 7.27-7.22 (m, 2H), 6.96 (d, J=7.2Hz, 1H), 6.46 (s, 1H), 6.11-6.07 (m, 1H), 2.64 (d, J=4.8 Hz, 3H), 2.11(s, 3H). MS (ESI) m/z [M+H]⁺ 351.9.

XLVI-4a was prepared following the similar procedure for obtainingXLVI-4 by using (4-nitrophenyl)boronic acid in place of XLVI-2. MS (ESI)m/z (M+H)⁺ 294.9.

Compound 418: To the solution of XLVI-4a (500 mg, 1.7 mmol) in DCM (15mL) was added TMSNCO (978 mg, 8.5 mmol). The mixture was stirred at rtovernight. LCMS showed the reaction was completed. The mixture wasfiltered and concentrated. The residue was purified by prep-TLC(PE/EA=1/3) to afford Compound 418 (101 mg, 18% yield). ¹H NMR (DMSO-d₆,400 MHz) δ 8.70 (s, 1H), 7.48-7.39 (m, 5H), 7.28-7.20 (m, 4H), 6.41 (s,1H), 5.89 (s, 2H), 2.08 (s, 3H). MS (ESI) m/z [M+H]⁺ 337.9.

Compound 560 was prepared by reacting XLVI-4 with isocyanatoethane inDCM at rt overnight. ¹H NMR (DMSO-d₆, 400 MHz) δ 8.50 (s, 1H), 7.58 (s,1H), 7.46-7.41 (m, 3H), 7.33-7.24 (m, 4H), 6.95 (d, J=7.2 Hz, 1H), 6.45(s, 1H), 6.08 (d, J=7.2 Hz, 1H), 3.74 (m, 1H), 2.11 (s, 3H), 1.10 (d,J=6.4 Hz, 6H).

Compound 561 was prepared by reacting XLVI-4 with 2-isocyanatopropane inDCM at rt overnight. ¹H NMR (DMSO-d₆, 400 MHz) δ 8.62 (s, 1H), 7.56 (s,1H), 7.44-7.39 (m, 3H), 7.32-7.30 (m, 2H), 7.22 (t, J=8.8 Hz, 2H),6.94-6.92 (m, 1H), 6.43 (s, 1H), 6.15 (t, J=5.6 Hz, 1H), 3.11-3.04 (m,2H), 2.08 (s, 3H), 7.02 (t, J=7.2 Hz, 3H).

Additional compounds as shown in Table 1 were also prepared. Thoseskilled in the art will be able to recognize modifications of thedisclosed syntheses and to devise alternate routes based on thedisclosures herein.

Compound 666: ¹H NMR (CDCl₃, 400 MHz) δ 8.20-8.10 (m, 4H), 7.42-7.40 (m,2H), 7.27 (m, 2H). MS (ESI) m/z [M+H]⁺ 337.0.

Compound 667: ¹H NMR (CDCl₃, 400 MHz) δ 8.04-8.00 (m, 2H), 7.51-7.49 (m,1H), 7.20-7.15 (m, 2H), 6.90-6.85 (m, 2H), 4.14-4.09 (q, J=7.2 Hz, 2H),2.30 (s, 3H), 1.48-1.44 (t, J=7.2 Hz, 3H). MS (ESI) m/z [M+H]⁺ 311.0.

Compound 668: ¹H NMR (CDCl₃, 400 MHz) δ 8.26 (s, 1H), 7.90 (s, 1H), 6.79(t, J=8.0 Hz, 2H), 5.40 (s, 1H), 4.72 (d, J=8.0 Hz, 1H), 4.49-4.38 (m,2H), 3.94-3.90 (q, J=6.4 Hz, 1H), 3.81-3.66 (m, 4H), 2.75-2.65 (m, 1H),2.28-2.16 (m, 4H), 2.05-1.97 (m, 2H), 1.52-1.44 (m, 3H), 1.31-1.25 (m,3H). MS (ESI) m/z (M+H)⁺ 449.1. EE %: 95.5%.

Example 25 5-Haloalkyl Substituted Analogs (Scheme XLVII)

To a mixture of XLVII-1 (8.2 g, 50 mmol, 1 eq) in DMF (60 mL) was addedXLVII-2 (13.1 g, 75 mmol, 1.5 eq), K₂CO₃ (11.0 g, 80 mmol, 1.6 eq) andNaI (1.4 g, 9.3 mmol, 0.18 eq). The resulting mixture was refluxed for 4h under N₂. Then the mixture was cooled to rt and diluted with H₂O andextracted with EA. The combined organic phase was washed with brine,dried over Na₂SO₄, and filtrated. EA was evaporated to allow solidprecipitate out. The solid was filtered, and the filter cake was washedwith PE to give the pure XLVII-3 (11.2 g, 70%) as a brown solid. Thefiltrate was concentrated and purified by flash column chromatography(PE:EA=10:1˜1:1) to afford the XLVII-3′(1.7 g, 10.6%) as a yellow oil.

The mixture of XLVII-3 (9.85 g, 31 mmol, 1 eq) and reductive iron power(5.2 g, 93 mmol, 3 eq) in 80 mL of 50% EtOH was heated to reflux,conc.HCl (0.34 mL, 4 mmol) was added dropwise, then the mixture wasrefluxed for 4 h. Then the mixture was cooled to rt, filtered, washedthe filter cake with EA, the filtrate was washed with brine, dried overNa₂SO₄, and concentrated to afford XLVII-4 (8.9 g, crude yield 100%).

The mixture of XLVII-4 (6.0 g, 20.8 mmol, 1 eq), chloroethanol (20 mL,300 mmol, 14.4 eq) and K₂CO₃ (5.75 g, 41.6 mmol, 2 eq) in DMF (50 mL)was stirred at 130° C. for 28 h. After the mixture was cooled to rt,diluted with H₂O, and extracted with EA, the filtrate was concentratedand the residue was purified to afford XLVII-5 (2.5 g, 36%) as a yellowsolid.

The mixture of XLVII-5 (2.0 g, 6 mmol, 1 eq), SOCl₂ (0.65 mL, 9 mmol,1.5 eq) and Et₃N (1.3 mL, 9 mmol, 1.5 eq) in DCM (50 mL) was stirred atrt for 28 h under N₂. The reaction was then quenched with H₂O, extractedwith EA, the filtrate was concentrated and the residue was purified toproduce XLVII-6 (1.5 g, 71%) as a yellow solid.

The mixture of XLVII-6 (900 mg, 2.6 mmol, 1 eq), XLVII-7 (1.2 g, 7.8mmol, 3 eq) and NaI (30 mg, catalytic amount) in CH₃CN (50 mL) wasrefluxed for 16 h under N₂. The solvent was then removed and theresulting residue was purified to give Compound 709 (420 mg, 37%) as ayellow colloid substance. ¹H NMR (CDCl₃, 400 MHz) δ 7.61 (s, 1H), 7.51(dd, J=2.6, 9.7 Hz, 1H), 7.11 (d, J=8.5 Hz, 1H), 6.76-6.70 (m, 2H), 6.58(dd, J=2.6, 8.7 Hz, 1H), 4.74 (t, J=4.5 Hz, 1H), 3.66-3.60 (m, 2H), 3.16(q, J=5.3 Hz, 2H), 2.72-2.44 (m, 12H). MS (ESI) m/z (M+H⁺) 445.1.

Example 26 ET-1 Assay

Assay of Inhibitory Effect on TGF-b induced Endothelin-1 Production

Fibroblasts (primary human lung and dermal, HFL-1, 3T3 etc) are seededin 96-well plates at ˜15000 cells/well and serum starved for 0-48 hours.After media exchange, compounds serially diluted in DMSO are added tothe cells. After a brief incubation of ˜30 min, stimulants (TGFb, serum,LPA etc) are added followed by further incubation for 16-48 hours. Mediais then harvested and stored frozen in plate format for laterendothelin-1 (ET-1) determination by ELISA. Toxicity measurements aremade using the ATPlite kit (Perkin-Elmer). ET-1 is quantified using anELISA kit (R&D Systems). The amount of ET-1 produced in the assay wellsare back-calculated using the ELISA standard. The ability of a compoundto inhibit ET-1 production is typically analyzed by fittingdose-response curves to a 4-parameter logistic function to obtain anEC50 value. A measure of cytotoxicity (CC50) is likewise reported fromthe same experiment using the ATPlite data.

Assay Data for Compounds

Compounds of some embodiments were prepared according to syntheticmethods described herein and assay data obtained for EC₅₀ against ET-1.The assay data obtained is presented in Table 2, in which A=less than 50μM, B=greater than or equal to 50 μM and less than or equal to 200 μM;and C=greater than 200 μM.

TABLE 2 EC₅₀ Compd. # ET-1 10 C 11 C 12 C 13 C 14 C 15 C 17 C 18 C 19 B21 C 22 C 23 B 24 C 25 C 26 A 27 C 28 B 29 B 31 A 32 C 33 A 34 A 35 A 36A 37 B 38 C 39 A 40 C 42 C 43 A 44 C 45 C 46 A 47 A 49 A 50 C 51 C 52 C53 C 54 C 55 C 56 C 57 C 58 A 59 A 60 A 61 A 62 C 63 A 64 B 65 C 66 B 67C 68 C 71 C 73 A 74 B 75 B 77 B 78 C 79 A 80 B 81 B 82 C 83 C 84 C 85 C86 B 87 A 88 B 89 C 90 C 91 C 92 B 93 A 94 C 95 A 96 C 97 C 98 B 99 A100 A 101 C 102 C 103 C 104 C 105 C 106 C 107 C 108 C 110 C 111 C 112 C113 C 114 C 115 C 116 C 118 C 119 A 120 A 121 C 122 C 123 A 124 C 125 C126 A 127 C 128 A 129 B 130 C 131 C 132 C 133 B 134 A 135 B 136 B 137 C138 C 139 C 140 B 141 C 143 C 144 C 145 B 146 C 147 C 148 C 149 B 150 B151 A 152 B 153 A 154 C 156 C 157 A 158 C 159 C 160 B 161 A 162 A 163 A164 A 165 B 166 A 167 C 168 B 169 B 170 A 171 B 172 C 173 C 174 A 175 B176 B 177 B 178 B 180 B 181 C 182 C 183 C 184 B 185 B 186 A 187 B 188 A189 C 190 B 191 B 192 A 193 B 194 A 195 A 196 B 197 B 198 B 199 B 200 B201 B 202 B 203 A 204 A 205 B 206 B 207 B 208 B 209 A 210 A 211 C 212 B213 C 214 B 216 B 217 C 218 A 219 B 220 C 221 C 222 C 223 C 224 C 225 C226 C 227 C 228 B 229 B 230 C 231 B 232 C 233 C 234 C 235 B 236 B 237 B238 B 240 C 241 C 242 C 243 B 244 C 247 C 248 C 250 B 251 A 252 B 253 C254 A 255 C 256 C 257 C 258 A 259 B 260 B 261 C 262 B 263 A 264 C 265 C266 C 267 C 268 C 269 C 270 C 271 C 272 C 273 C 274 C 275 C 276 C 277 C278 B 279 C 281 C 282 C 283 C 285 C 287 C 288 B 289 B 290 B 291 C 294 B296 C 298 B 299 C 300 C 302 B 303 B 309 B 310 B 311 C 312 C 313 B 314 A315 A 316 A 318 A 319 A 320 A 321 A 322 A 323 C 324 B 327 C 328 C 329 C330 C 331 C 332 C 333 B 334 C 336 C 338 C 344 C 345 C 346 C 347 B 349 C350 B 351 A 352 B 353 B 354 B 355 C 356 B 357 C 359 C 360 A 361 C 362 C363 C 364 C 365 C 366 C 367 C 368 C 369 B 370 C 371 C 372 C 373 C 374 A375 C 376 A 377 B 378 B 379 C 380 C 381 C 382 B 383 B 384 B 385 B 387 B388 C 390 C 391 A 392 C 393 C 394 A 395 B 396 C 397 C 398 C 399 C 400 A401 C 402 A 403 A 404 A 405 A 406 B 407 A 408 C 409 A 410 A 411 B 412 C413 A 414 A 415 A 416 A 417 A 418 B 419 B 420 B 421 B 422 C 423 C 424 B425 A 426 C 427 C 429 C 430 A 431 C 432 C 438 C 439 C 440 C 442 C 526 C527 A 528 A 529 C 530 A 531 A 532 A 533 B 534 A 535 A 536 A 537 A 540 A541 C 542 A 543 A 544 B 545 C 546 C 547 A 550 A 552 C 553 A 554 C 555 C556 C 557 A 558 B 559 A 562 A 563 A 565 A 566 C 568 C 569 A 570 C 571 C573 C 574 A 575 A 577 B 579 C 580 A 581 C 582 A 583 A 584 A 585 C 586 A587 A 588 C 591 A 593 A 594 A 595 A 596 A 597 C 598 A 599 A 600 A 601 A602 A 603 A 604 A 605 A 606 A 607 A 608 B 609 A 610 A 611 A 612 A 614 A615 A 617 A 618 B 619 A 620 A 622 C 623 C 624 A 625 A 626 A 628 A 629 A631 A 634 A 636 C 647 A 648 A 649 A 650 A 651 A 657 A 665 A 666 A 667 A669 A 670 A 671 A 672 A 673 A 674 B 675 A 676 A 677 B 678 B 679 A 680 C681 B 682 A 683 A 684 B 685 A 686 B 687 A 688 B 689 A 690 A 691 A 692 A693 B 694 A 695 A 696 B 697 B 698 B 699 B 700 B 701 A 702 A 703 A 704 A705 A 706 A 707 A 708 B 709 B

Example 27 Cell Proliferation Assay

Assay of Inhibitory Effect on Cell Proliferation (BrdU Incorporation)

Fibroblasts (primary human lung and dermal, HFL-1, 3T3 etc) were platedon a 96-well plate and serum starved for 24-48 hours. The media werethen exchanged for media containing stimulants (LPA, TGFb, serum etc)and cultured further for 16-24 hours before BrdU addition. Afterculturing for another 8 hours, cells were washed with PBS and the amountof BrdU incorporated into the cells was assayed by absorbance at 450 nmusing the Cell proliferation ELISA system (RPN250, Amersham LIFESCIENCE). The difference between the amount of BrdU incorporated in thestimulant-added well and the amount of BrdU incorporated in the wellcontaining no stimulant represented the amount of BrdU incorporationaccelerated by stimulant. The increase of BrdU incorporation without theaddition of test compounds was set as 100% and the concentration ofcompound with 50% inhibition in the increase of BrdU incorporation (IC₅₀value) was determined. The test compounds were added 0-30 min beforestimulant addition.

Assay Data for Compounds

Compounds of some embodiments were prepared according to syntheticmethods described herein and assay data obtained for IC₅₀ for BrdUinhibition. The assay data obtained is presented in Table 3, in whichA=less than 50 μM, B=greater than or equal to 50 μM and less than orequal to 200 μM; and C=greater than 200 μM.

TABLE 3 Compd. # IC₅₀ BRDU 13 C 21 C 28 B 29 C 31 B 41 A 43 C 46 A 47 A49 A 50 A 51 C 52 C 53 C 58 A 59 A 60 A 61 A 63 A 68 C 71 C 73 C 75 B 80C 86 A 87 A 101 B 119 A 120 A 123 A 126 A 133 B 134 A 153 A 155 A 157 C160 A 161 A 162 A 175 A 180 A 184 A 185 A 188 A 189 C 192 A 195 A 196 A198 A 201 A 202 A 203 A 204 A 206 A 207 A 208 B 209 A 210 C 216 A 218 A219 C 229 A 234 C 237 A 238 A 239 A 243 C 251 A 252 B 254 A 258 A 259 A260 A 261 A 262 A 263 A 276 C 278 B 282 C 285 C 290 C 300 C 316 A 333 C350 B 351 B 353 C 360 B 374 B 376 C 383 B 385 A 387 B 391 B 394 A 395 B399 A 400 A 402 C 403 A 404 A 405 A 406 A 407 A 410 A 411 A 413 A 414 A415 A 416 A 417 A 418 B 419 B 424 A 425 A 430 A 431 B 432 B 531 A 535 A538 B 542 A 543 A 544 A 547 A 550 A 551 A 553 A 557 A 562 A 563 A 564 A565 A 569 A 570 C 574 A 575 A 583 A 584 A 588 A 591 C 594 A 595 B 600 C601 A 602 A 603 A 604 A 605 A 606 A 607 A 609 A 610 A 615 A 617 B 618 B619 A 620 A 624 A 625 A 626 A 629 C 631 C 636 C 640 C 647 A 648 A 649 B650 A 651 A 657 A 658 C 662 C 664 A 665 B 681 A 682 A 683 A 684 A 685 A686 A 687 A 688 B 689 A

While the disclosure has been illustrated and described in detail in theforegoing description, such illustration and description are to beconsidered illustrative or exemplary and not restrictive. The disclosureis not limited to the disclosed embodiments. Variations to the disclosedembodiments can be understood and effected by those skilled in the artin practicing the claimed disclosure, from a study of the drawings, thedisclosure and the appended claims.

All references cited herein are incorporated herein by reference intheir entirety. To the extent publications and patents or patentapplications incorporated by reference contradict the disclosurecontained in the specification, the specification is intended tosupersede and/or take precedence over any such contradictory material.

Unless otherwise defined, all terms (including technical and scientificterms) are to be given their ordinary and customary meaning to a personof ordinary skill in the art, and are not to be limited to a special orcustomized meaning unless expressly so defined herein. It should benoted that the use of particular terminology when describing certainfeatures or aspects of the disclosure should not be taken to imply thatthe terminology is being re-defined herein to be restricted to includeany specific characteristics of the features or aspects of thedisclosure with which that terminology is associated.

Where a range of values is provided, it is understood that the upper andlower limit, and each intervening value between the upper and lowerlimit of the range is encompassed within the embodiments.

Terms and phrases used in this application, and variations thereof,especially in the appended claims, unless otherwise expressly stated,should be construed as open ended as opposed to limiting. As examples ofthe foregoing, the term ‘including’ should be read to mean ‘including,without limitation,’ ‘including but not limited to,’ or the like; theterm ‘comprising’ as used herein is synonymous with ‘including,’‘containing,’ or ‘characterized by,’ and is inclusive or open-ended anddoes not exclude additional, unrecited elements or method steps; theterm ‘having’ should be interpreted as ‘having at least;’ the term‘includes’ should be interpreted as ‘includes but is not limited to;’the term ‘example’ is used to provide exemplary instances of the item indiscussion, not an exhaustive or limiting list thereof; adjectives suchas ‘known’, ‘normal’, ‘standard’, and terms of similar meaning shouldnot be construed as limiting the item described to a given time periodor to an item available as of a given time, but instead should be readto encompass known, normal, or standard technologies that may beavailable or known now or at any time in the future; and use of termslike ‘preferably,’ preferred, ‘desired,’ or ‘desirable,’ and words ofsimilar meaning should not be understood as implying that certainfeatures are critical, essential, or even important to the structure orfunction of the invention, but instead as merely intended to highlightalternative or additional features that may or may not be utilized in aparticular embodiment of the invention. Likewise, a group of itemslinked with the conjunction ‘and’ should not be read as requiring thateach and every one of those items be present in the grouping, but rathershould be read as ‘and/or’ unless expressly stated otherwise. Similarly,a group of items linked with the conjunction ‘or’ should not be read asrequiring mutual exclusivity among that group, but rather should be readas ‘and/or’ unless expressly stated otherwise.

With respect to the use of substantially any plural and/or singularterms herein, those having skill in the art can translate from theplural to the singular and/or from the singular to the plural as isappropriate to the context and/or application. The varioussingular/plural permutations may be expressly set forth herein for sakeof clarity. The indefinite article “a” or “an” does not exclude aplurality. A single processor or other unit may fulfill the functions ofseveral items recited in the claims. The mere fact that certain measuresare recited in mutually different dependent claims does not indicatethat a combination of these measures cannot be used to advantage. Anyreference signs in the claims should not be construed as limiting thescope.

It will be further understood by those within the art that if a specificnumber of an introduced claim recitation is intended, such an intentwill be explicitly recited in the claim, and in the absence of suchrecitation no such intent is present. For example, as an aid tounderstanding, the following appended claims may contain usage of theintroductory phrases “at least one” and “one or more” to introduce claimrecitations. However, the use of such phrases should not be construed toimply that the introduction of a claim recitation by the indefinitearticles “a” or “an” limits any particular claim containing suchintroduced claim recitation to embodiments containing only one suchrecitation, even when the same claim includes the introductory phrases“one or more” or “at least one” and indefinite articles such as “a” or“an” (e.g., “a” and/or “an” should typically be interpreted to mean “atleast one” or “one or more”); the same holds true for the use ofdefinite articles used to introduce claim recitations. In addition, evenif a specific number of an introduced claim recitation is explicitlyrecited, those skilled in the art will recognize that such recitationshould typically be interpreted to mean at least the recited number(e.g., the bare recitation of “two recitations,” without othermodifiers, typically means at least two recitations, or two or morerecitations). Furthermore, in those instances where a conventionanalogous to “at least one of A, B, and C, etc.” is used, in generalsuch a construction is intended in the sense one having skill in the artwould understand the convention (e.g., “a system having at least one ofA, B, and C” would include but not be limited to systems that have Aalone, B alone, C alone, A and B together, A and C together, B and Ctogether, and/or A, B, and C together, etc.). In those instances where aconvention analogous to “at least one of A, B, or C, etc.” is used, ingeneral such a construction is intended in the sense one having skill inthe art would understand the convention (e.g., “a system having at leastone of A, B, or C” would include but not be limited to systems that haveA alone, B alone, C alone, A and B together, A and C together, B and Ctogether, and/or A, B, and C together, etc.). It will be furtherunderstood by those within the art that virtually any disjunctive wordand/or phrase presenting two or more alternative terms, whether in thedescription, claims, or drawings, should be understood to contemplatethe possibilities of including one of the terms, either of the terms, orboth terms. For example, the phrase “A or B” will be understood toinclude the possibilities of “A” or “B” or “A and B.”

All numbers expressing quantities of ingredients, reaction conditions,and so forth used in the specification are to be understood as beingmodified in all instances by the term ‘about.’ Accordingly, unlessindicated to the contrary, the numerical parameters set forth herein areapproximations that may vary depending upon the desired propertiessought to be obtained. At the very least, and not as an attempt to limitthe application of the doctrine of equivalents to the scope of anyclaims in any application claiming priority to the present application,each numerical parameter should be construed in light of the number ofsignificant digits and ordinary rounding approaches.

Furthermore, although the foregoing has been described in some detail byway of illustrations and examples for purposes of clarity andunderstanding, it is apparent to those skilled in the art that certainchanges and modifications may be practiced. Therefore, the descriptionand examples should not be construed as limiting the scope of theinvention to the specific embodiments and examples described herein, butrather to also cover all modification and alternatives coming with thetrue scope and spirit of the invention.

What is claimed is:
 1. A method of treating a fibrotic conditionselected from pulmonary fibrosis, dermal fibrosis, pancreatic fibrosis,liver fibrosis, and renal fibrosis, comprising administering atherapeutically effective amount of a compound having the structure ofFormula (III):

or a pharmaceutically acceptable salt thereof to a subject in needthereof, wherein R¹ is selected from the group consisting of C₆₋₁₀ aryloptionally substituted with one or more R⁴, 5-10 membered heteroaryloptionally substituted with one or more R⁴, C₃₋₁₀ carbocyclyl optionallysubstituted with one or more R⁴, and 3-10 membered heterocyclyloptionally substituted with one or more R⁴; R³ is selected from thegroup consisting of hydrogen, —(CH₂)_(n)—(C₆₋₁₀ aryl), —(CH₂)_(n)-(5-10membered heteroaryl), —(CH₂)_(n)—(C₃₋₁₀ carbocyclyl), and—(CH₂)_(n)—(3-10 membered heterocyclyl), each optionally substitutedwith one or more R⁹; ring A is

optionally substituted with one or more R⁴, wherein R¹⁷ is independentlyselected from hydrogen, optionally substituted C₁₋₆ alkyl, optionallysubstituted C₃₋₆ cycloalkyl, optionally substituted C₂₋₈ alkoxyalkyl,optionally substituted C-carboxy, acyl, C₆₋₁₀ aryl optionallysubstituted with one or more R¹¹, or C₇₋₁₄ aralkyl optionallysubstituted with one or more R¹¹, each R⁴ is independently selected fromthe group consisting of halogen, —CN, —OH, —C(O)R⁸, —SO₂R¹⁶, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl, optionallysubstituted C₂₋₆ alkynyl, optionally substituted C₁₋₆ alkoxy, optionallysubstituted C₆₋₁₀ aryl optionally substituted with one or more R¹¹,C₇₋₁₄ aralkyl optionally substituted with one or more R¹¹, 5-10 memberedheteroaryl optionally substituted with one or more R¹¹, or independentlytwo geminal R⁴ together are oxo; each R⁵ is independently selected fromthe group consisting of hydrogen, optionally substituted C₁₋₆ alkyl,optionally substituted C₂₋₆ alkenyl, optionally substituted C₂₋₆alkynyl, optionally substituted C₂₋₈ alkoxyalkyl, C₆₋₁₀ aryl optionallysubstituted with one or more R¹¹, C₇₋₁₄ aralkyl optionally substitutedwith one or more R¹¹, and —(CH₂)_(n)-(3-10 membered heterocyclyl)optionally substituted with one or more R¹⁰; each R⁸ is independentlyselected from the group consisting of hydrogen, optionally substitutedC₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl, optionally substitutedC₂₋₆ alkynyl, C₆₋₁₀ aryl optionally substituted with one or more R¹¹,C₇₋₁₄ aralkyl optionally substituted with one or more R¹¹, —NR¹²R¹³, and—OR⁵; each R⁹ is independently selected from the group consisting ofhydroxy, halogen, optionally substituted C₁₋₆ alkyl, optionallysubstituted C₂₋₆ alkenyl, optionally substituted C₂₋₆ alkynyl,optionally substituted C₁₋₆ alkylthio, optionally substituted C₂₋₈alkoxyalkyl, optionally substituted C₃₋₁₀ carbocyclyl, optionallysubstituted C₆₋₁₀ aryl, —OR⁵, —NR¹⁴R¹⁵, —C(O)R⁸, —SO₂R¹⁶, —CN, and —NO₂;each R¹⁰ is independently selected from the group consisting ofoptionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl,and optionally substituted C₂₋₆ alkynyl, or independently two geminalR¹⁰ together are oxo; each R¹¹ is independently selected from the groupconsisting of halogen, —CN, optionally substituted C₁₋₆ alkyl,optionally substituted C₂₋₆ alkenyl, optionally substituted C₂₋₆alkynyl, and optionally substituted C₁₋₆ alkoxy; each R¹² isindependently selected from the group consisting of hydrogen, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl, optionallysubstituted C₂₋₆ alkynyl, C₆₋₁₀ aryl optionally substituted with one ormore R¹¹, and C₇₋₁₄ aralkyl optionally substituted with one or more R¹¹;each R¹³ is independently selected from the group consisting ofhydrogen, optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆alkenyl, optionally substituted C₂₋₆ alkynyl, C₆₋₁₀ aryl optionallysubstituted with one or more R¹¹, and C₇₋₁₄ aralkyl optionallysubstituted with one or more R¹¹; R¹⁴ is selected from the groupconsisting of hydrogen, optionally substituted C₁₋₆ alkyl, optionallysubstituted C₆₋₁₀ aryl, and —C(O)R⁸; R¹⁵ is selected from the groupconsisting of hydrogen, optionally substituted C₁₋₆ alkyl, optionallysubstituted C₆₋₁₀ aryl, and —C(O)R⁸; each R¹⁶ is independently selectedfrom the group consisting of optionally substituted C₁₋₆ alkyl,optionally substituted C₂₋₆ alkenyl, optionally substituted C₂₋₆alkynyl, C₆₋₁₀ aryl optionally substituted with one or more R¹¹, C₇₋₁₄aralkyl optionally substituted with one or more R¹¹, —NR¹²R¹³, and —OR⁵;Z is selected from oxygen and sulfur; each n is 0; and the bondsrepresented by a solid and dashed line are independently selected fromthe group consisting of a single bond and a double bond.
 2. The methodof claim 1, wherein R³ is selected from the group consisting of—(CH₂)_(n)—(C₆₋₁₀ aryl), —(CH₂)_(n)-(5-10 membered heteroaryl),—(CH₂)_(n)—(C₃₋₁₀ carbocyclyl), and —(CH₂)_(n)-(3-10 memberedheterocyclyl), each optionally substituted with one or more R⁹; and eachR⁹ is independently selected from the group consisting of halogen,optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl,optionally substituted C₂₋₆ alkynyl, optionally substituted C₁₋₆alkylthio, optionally substituted C₂₋₈ alkoxyalkyl, optionallysubstituted C₃₋₁₀ carbocyclyl, optionally substituted C₆₋₁₀ aryl, —OR⁵,—NR¹⁴R¹⁵, —C(O)R⁸, —SO₂R¹⁶, and —NO₂.
 3. The method of claim 1, whereinR¹ is selected from C₆₋₁₀ aryl optionally substituted with one or moreR⁴, or 5 to 6 membered heteroaryl optionally substituted with one ormore R⁴.
 4. The method of claim 3, wherein R¹ is phenyl optionallysubstituted with one or more R⁴.
 5. The method of claim 3, wherein R¹ ispyridazinyl optionally substituted with one or more R⁴.
 6. The method ofclaim 3, wherein R¹ is pyrazolyl or 1-methyl pyrazolyl optionallysubstituted with one or more R⁴.
 7. The method of claim 1, wherein R³ is—(CH₂)_(n)—(C₆₋₁₀ aryl) optionally substituted with one or more R⁹. 8.The method of claim 7, wherein R³ is phenyl, optionally substituted withone or more R⁹.
 9. The method of claim 7, wherein R³ is unsubstituted.10. The method of claim 8, wherein R⁹ is selected from cyano, halogen,optionally substituted C₁₋₆ alkyl, or optionally substituted C₁₋₆alkoxy.
 11. The method of claim 10, wherein R⁹ is selected from cyano,fluoro, chloro, methyl, ethyl, ethoxy, methoxy, trifluoromethyl,trifluoromethoxy or difluoromethoxy.
 12. The method of claim 1, whereinR¹⁷ is selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl,—(CH₂)₂F, —(CH₂)₂OH, —(CH₂)₂OCH₃, —(CH₂)₂OC₂H₅, —(CH₂)₂OC₃H₇,—C(O)O-t-Bu, —C(O)CH₃ or benzyl.
 13. The method of claim 1, wherein R⁴is selected from halogen, optionally substituted C₁₋₆ alkyl, or C₇₋₁₄aralkyl optionally substituted with one or more R¹¹, or two geminal R⁴together are oxo.
 14. The method of claim 13, wherein R⁴ is selectedfrom fluoro, methyl, trifluoromethyl, —(CH₂)₂OH, benzyl, or two geminalR⁴ together are oxo.
 15. The method of claim 1, wherein ring A isunsubstituted.
 16. The method of claim 1, wherein Z is oxygen.
 17. Themethod of claim 1, wherein the bonds represented by a solid and dashedline are double bonds.
 18. The method of claim 1, wherein the compoundis selected from the group consisting of

or pharmaceutically acceptable salts thereof.
 19. The method of claim18, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 20. The method of claim18, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 21. The method of claim18, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 22. The method of claim18, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 23. The method of claim1, wherein the fibrotic condition is idiopathic pulmonary fibrosis. 24.The method of claim 1, wherein the compound is administered byinhalation.